VCV000065385.46 - ClinVar

NM_001322934.2(NFKB2):c.2557C>T (p.Arg853Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001322934.2(NFKB2):c.2557C>T (p.Arg853Ter)

Variation ID: 65385 Accession: VCV000065385.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q24.32 10: 102402138 (GRCh38) [ NCBI UCSC ] 10: 104161895 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 18, 2013	Oct 20, 2024	Sep 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001322934.2:c.2557C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001309863.1:p.Arg853Ter	nonsense
NM_001077494.3:c.2557C>T	NP_001070962.1:p.Arg853Ter	nonsense
NM_001261403.3:c.2557C>T	NP_001248332.1:p.Arg853Ter	nonsense
NM_001288724.1:c.2557C>T	NP_001275653.1:p.Arg853Ter	nonsense
NM_001322935.1:c.2431C>T	NP_001309864.1:p.Arg811Ter	nonsense
NM_002502.6:c.2557C>T	NP_002493.3:p.Arg853Ter	nonsense
NC_000010.11:g.102402138C>T
NC_000010.10:g.104161895C>T
NG_033874.2:g.13029C>T
LRG_1347:g.13029C>T
LRG_1347t1:c.2557C>T	LRG_1347p1:p.Arg853Ter

... more HGVS ... less HGVS

Protein change

R853*, R811*

Other names

Canonical SPDI

NC_000010.11:102402137:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

dominant_negative_variant; Sequence Ontology [ SO:0002052]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 164012.0002 dbSNP: rs397514332 ClinGen: CA144753 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NFKB2		-	-	GRCh38 GRCh37	549	693
PSD		-	-	GRCh38 GRCh37	66	93

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2016	RCV000055612.16
Immunodeficiency, common variable, 10	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Sep 25, 2024	RCV000077761.28
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 15, 2022	RCV001093426.29
Inherited Immunodeficiency Diseases	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2019	RCV001027606.9
Common variable immunodeficiency	Pathogenic (1)	criteria provided, single submitter	Jan 9, 2020	RCV001174741.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 10 Affected status: yes Allele origin: unknown	Molecular Genetics Laboratory - Diagnostics Genetics, LabPLUS - Auckland City Hospital Accession: SCV002575024.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Clinical Features: CVID (present) Age: 0-9 years Sex: female Ethnicity/Population group: Maori Geographic origin: New Zealand
Pathogenic (Jul 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002549308.2 First in ClinVar: Jul 23, 2022 Last updated: Mar 04, 2023	Comment: Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost, and other loss-of-function variants have been … (more) Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); In vitro assays demonstrated that R853X has a dominant negative effect (Kuehn et al., 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24702956, 25605273, 27577878, 28778864, 28983403, 29225085, 30941118, 30078247, 28919517, 30267444, 24140114, 25524009, 30500415, 29952021, 32135276, 32499645, 32888943, 32694887) (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Immunodeficiency, common variable, 10 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804996.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Sep 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 10 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV005328352.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Clinical Features: Apraxia (present) , Memory impairment (present) , Alzheimer disease (present) , Recurrent infections (present) , Immunodeficiency (present) , Autoimmunity (present) , Generalized cerebral atrophy/hypoplasia (present) … (more) Apraxia (present) , Memory impairment (present) , Alzheimer disease (present) , Recurrent infections (present) , Immunodeficiency (present) , Autoimmunity (present) , Generalized cerebral atrophy/hypoplasia (present) , Alopecia totalis (present) , Chronic sinusitis (present) , Abnormally slow thought process (present) , Elevated CSF neurofilament light chain concentration (present) , Impaired executive functioning (present) , Dementia (present) (less)
Pathogenic (Dec 15, 2016)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000083837.2 First in ClinVar: Sep 18, 2013 Last updated: Sep 18, 2013
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Inherited Immunodeficiency Diseases Affected status: yes Allele origin: germline	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001190180.1 First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020	Clinical Features: Immunodeficiency (present)
Pathogenic (Jan 09, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Common variable immunodeficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001338047.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (3) PubMed: 24140114‚ 30941118‚ 28778864 Comment: Variant summary: NFKB2 c.2557C>T (p.Arg853X) results in a premature termination codon, and though it is not expected to cause nonsense mediated decay (NMD), it is … (more) Variant summary: NFKB2 c.2557C>T (p.Arg853X) results in a premature termination codon, and though it is not expected to cause nonsense mediated decay (NMD), it is predicted to cause a truncation of the encoded protein. The variant was absent in 187640 control chromosomes (gnomAD). c.2557C>T has been reported in the literature in numerous individuals affected with Common Variable Immunodeficiency (e.g. Chen_2013, Klemann_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this C-terminal truncation indeed affects normal protein function (Chen_2013, Kuehn_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 10 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001425340.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020	Publications: PubMed (5) PubMed: 24140114‚ 25524009‚ 28778864‚ 29225085‚ 30941118
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 10 Affected status: yes Allele origin: unknown	3billion Accession: SCV003841639.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 24140114 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function … (more) The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000065385 / PMID: 24140114). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Tip-toe gait (present) , Skeletal myopathy (present) , Distal muscle weakness (present) , Difficulty walking (present) , Hypothyroidism (present) , Elevated circulating creatine kinase concentration … (more) Tip-toe gait (present) , Skeletal myopathy (present) , Distal muscle weakness (present) , Difficulty walking (present) , Hypothyroidism (present) , Elevated circulating creatine kinase concentration (present) (less)
Pathogenic (Sep 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunodeficiency, common variable, 10 (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Bioinformatics Unit, Institut Pasteur de Montevideo Accession: SCV004031475.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023	Comment: We found this variant in three affected family members and not present in an unaffected one. Number of individuals with the variant: 3 Sex: male Geographic origin: Uruguay
Pathogenic (Nov 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Immunodeficiency, common variable, 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000773792.7 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 24702956‚ 25524009‚ 25605273‚ 24140114‚ 28778864 Comment: This sequence change creates a premature translational stop signal (p.Arg853) in the NFKB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg853) in the NFKB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the NFKB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with NFKB2-related immunodeficiencies (PMID: 24702956, 25524009, 25605273). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65385). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NFKB2 function (PMID: 24140114, 28778864). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250394.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Dec 19, 2014)	no assertion criteria provided Method: literature only	IMMUNODEFICIENCY, COMMON VARIABLE, 10 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000109567.3 First in ClinVar: Dec 24, 2013 Last updated: Jan 31, 2019	Publications: PubMed (2) PubMed: 24140114‚ 25524009 Comment on evidence: In a patient of northern European descent with common variable immunodeficiency-10 (CVID10; 615577), Chen et al. (2013) identified a heterozygous c.2557C-T transition in the NFKB2 … (more) In a patient of northern European descent with common variable immunodeficiency-10 (CVID10; 615577), Chen et al. (2013) identified a heterozygous c.2557C-T transition in the NFKB2 gene, resulting in an arg853-to-ter (R853X) substitution. This patient was identified from a cohort of 33 individuals with CVID who were tested for variants in the NFKB2 gene. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases or in 50 control exomes. The unaffected mother did not carry the mutation; DNA from the father was unavailable. The mutation caused a truncation in the C terminus of the protein, removing the conserved phosphorylation sites required for activation of p100 to p52. Cell lines carrying the mutation lacked the phosphorylated signal observed in control cells. The mutant truncated protein could not be processed by the proteasome, resulting in reduced protein activation and nuclear translocation. In a boy with CVID10, Brue et al. (2014) identified a de novo heterozygous R853X mutation in the NFKB2 gene within the C-terminal NIK (MAP3K14; 604655) response domain. The patient also had hair loss and low ACTH; brain MRI showed a hypoplastic anterior pituitary. Functional studies of the variant were not performed. (less)
Pathogenic (-)	no assertion criteria provided Method: research	Combined variable immunodeficiency (CVID) with pituitary insufficiency (ACTH deficiency, sometimes with growth hormone or thyroid hormone deficiency) Affected status: yes Allele origin: unknown	Samuels research lab, Centre de Recherche du CHU Ste-Justine Study: FORGE Canada Accession: SCV000172088.1 First in ClinVar: Jan 28, 2015 Last updated: Jan 28, 2015 Comment: Molecular characterization of rare pediatric disorders in Canada	Publications: PubMed (1) PubMed: 25524009 Number of individuals with the variant: 1 Geographic origin: Italy
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Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); In vitro assays demonstrated that R853X has a dominant negative effect (Kuehn et al., 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24702956, 25605273, 27577878, 28778864, 28983403, 29225085, 30941118, 30078247, 28919517, 30267444, 24140114, 25524009, 30500415, 29952021, 32135276, 32499645, 32888943, 32694887)

Comment:

Variant summary: NFKB2 c.2557C>T (p.Arg853X) results in a premature termination codon, and though it is not expected to cause nonsense mediated decay (NMD), it is predicted to cause a truncation of the encoded protein. The variant was absent in 187640 control chromosomes (gnomAD). c.2557C>T has been reported in the literature in numerous individuals affected with Common Variable Immunodeficiency (e.g. Chen_2013, Klemann_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this C-terminal truncation indeed affects normal protein function (Chen_2013, Kuehn_2017). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000065385 / PMID: 24140114). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Arg853*) in the NFKB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the NFKB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with NFKB2-related immunodeficiencies (PMID: 24702956, 25524009, 25605273). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65385). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NFKB2 function (PMID: 24140114, 28778864). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
dominant_negative_variant (SO:0002052)			Molecular Genetics Laboratory - Diagnostics Genetics, LabPLUS - Auckland City Hospital Accession: SCV002575024.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.	Klemann C	Frontiers in immunology	2019	PMID: 30941118
Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation.	Ramakrishnan KA	The Journal of allergy and clinical immunology	2018	PMID: 29225085
Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype.	Kuehn HS	Blood	2017	PMID: 28778864
Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease.	Lougaris V	The Journal of allergy and clinical immunology	2015	PMID: 25605273
Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.	Brue T	BMC medical genetics	2014	PMID: 25524009
Phevor combines multiple biomedical ontologies for accurate identification of disease-causing alleles in single individuals and small nuclear families.	Singleton MV	American journal of human genetics	2014	PMID: 24702956
Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency.	Chen K	American journal of human genetics	2013	PMID: 24140114

Text-mined citations for rs397514332 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001322934.2(NFKB2):c.2557C>T (p.Arg853Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397514332 ...