VCV000158240.50 - ClinVar

NM_001194998.2(CEP152):c.2034T>G (p.Tyr678Ter)

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.

(17)

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/Likely 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_001194998.2(CEP152):c.2034T>G (p.Tyr678Ter)

Variation ID: 158240 Accession: VCV000158240.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 48767448 (GRCh38) [ NCBI UCSC ] 15: 49059645 (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	Nov 23, 2014	Oct 20, 2024	May 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001194998.2:c.2034T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001181927.1:p.Tyr678Ter	nonsense
NM_014985.4:c.2034T>G	NP_055800.2:p.Tyr678Ter	nonsense
NC_000015.10:g.48767448A>C
NC_000015.9:g.49059645A>C
NG_027518.2:g.48699T>G

... more HGVS ... less HGVS

Protein change

Y678*

Other names

Canonical SPDI

NC_000015.10:48767447:A:C

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

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.

0.00060 (C)

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

1000 Genomes Project 30x 0.00047

The Genome Aggregation Database (gnomAD) 0.00048

Trans-Omics for Precision Medicine (TOPMed) 0.00050

1000 Genomes Project 0.00060

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00073

Links

ClinGen: CA211025 OMIM: 613529.0004 dbSNP: rs182018947 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.
CEP152		-	-	GRCh38 GRCh37	1082	1111

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.
Microcephaly 9, primary, autosomal recessive	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 11, 2024	RCV000145609.20
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000286958.29
Seckel syndrome 5	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 18, 2016	RCV000490391.13
Microcephaly 9, primary, autosomal recessive Seckel syndrome 5	Pathogenic (1)	criteria provided, single submitter	May 18, 2017	RCV000515277.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2022	RCV004019767.1
CEP152-related disorder	Pathogenic (1)	criteria provided, single submitter	May 24, 2023	RCV004556749.1

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 (Jan 28, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Microcephaly 9, primary, autosomal recessive Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236533.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Jan 26, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329695.8 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30833958, 31980526, 25525159, 21131973, 27219052, 34426522) (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly 9, primary, autosomal recessive Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806962.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Likely pathogenic (May 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly 9, primary, autosomal recessive Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784549.3 First in ClinVar: Jul 02, 2015 Last updated: May 19, 2024	Number of individuals with the variant: 1 Age: 0-9 years Sex: male Geographic origin: Iran
Pathogenic (Jul 28, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly 9, primary, autosomal recessive (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000192706.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Likely pathogenic (Aug 15, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000863001.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 21131973 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CEP152 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly 9, primary, autosomal recessive Affected status: yes Allele origin: maternal	3billion Accession: SCV002012250.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Comment: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more) Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000295, PM2). The variant was observed in trans with a pathogenic variant (NM_001194998.1:c.314G>A) as compound heterozygous (3billion dataset, PM3).The variant has been reported as pathogenic (ClinVar ID: VCV000158240.10). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal facial shape (present) , Failure to thrive (present) , Hypertelorism (present) , Hamartoma of hypothalamus (present) , Hypothyroidism (present) , Microcephaly (present) , Micrognathia … (more) Abnormal facial shape (present) , Failure to thrive (present) , Hypertelorism (present) , Hamartoma of hypothalamus (present) , Hypothyroidism (present) , Microcephaly (present) , Micrognathia (present) , Precocious puberty (present) , Scoliosis (present) , Disproportionate short stature (present) , Small for gestational age (present) , Triangular face (present) , Intellectual disability, mild (present) (less)
Pathogenic (Sep 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017012.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003281289.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 21131973 Comment: This sequence change creates a premature translational stop signal (p.Tyr678) in the CEP152 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Tyr678) in the CEP152 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP152 are known to be pathogenic (PMID: 21131973). This variant is present in population databases (rs182018947, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with CEP152-related conditions (PMID: 21131973). ClinVar contains an entry for this variant (Variation ID: 158240). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 13, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004925456.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 21131973 Comment: The c.2034T>G (p.Y678) alteration, located in exon 16 (coding exon 15) of the CEP152 gene, consists of a T to G substitution at nucleotide position … (more) The c.2034T>G (p.Y678) alteration, located in exon 16 (coding exon 15) of the CEP152 gene, consists of a T to G substitution at nucleotide position 2034. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 678. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the compound heterozygous state with a second CEP152 alteration in a patient with clinical features of CEP152-related Seckel syndrome (Kalay, 2011). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (May 24, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	CEP152-related disorder Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV005045613.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024
Pathogenic (Feb 01, 2024)	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: SCV002822185.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: CEP152: PVS1, PM2, PM3 Number of individuals with the variant: 2
Pathogenic (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Seckel syndrome 5 Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267247.1 First in ClinVar: May 25, 2017 Last updated: May 25, 2017	Publications: PubMed (1) PubMed: 21131973 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seckel syndrome 5 Microcephaly 9, primary, autosomal recessive Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611256.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seckel syndrome 5 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004171351.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Comment: The stop gained c.2034T>G(p.Tyr678Ter) variant in CEP152 gene has been reported previously in compound heterozygous state in individual(s) affected with Seckel syndrome (Kalay E, et. … (more) The stop gained c.2034T>G(p.Tyr678Ter) variant in CEP152 gene has been reported previously in compound heterozygous state in individual(s) affected with Seckel syndrome (Kalay E, et. al., 2011; Fujikura K., 2016). The p.Tyr678Ter variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Signifiance / Likely Pathogenic / Pathogenic (multiple submissions). The nucleotide change c.2034T>G in CEP152 is predicted as conserved by GERP++. This sequence change creates a premature translational stop signal (p.Tyr678Ter) in the CEP152 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2011)	no assertion criteria provided Method: literature only	SECKEL SYNDROME 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045316.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016	Publications: PubMed (1) PubMed: 21131973 Comment on evidence: In a Seckel syndrome patient (SCKL5; 613823) of Italian origin living in Germany, Kalay et al. (2011) identified compound heterozygosity for 2 mutations in the … (more) In a Seckel syndrome patient (SCKL5; 613823) of Italian origin living in Germany, Kalay et al. (2011) identified compound heterozygosity for 2 mutations in the CEP152 gene: a 2034T-G transversion resulting in a tyr678-to-ter mutation (Y678X) and a splice site mutation at intron 19 (613529.0005). The splice site mutation (2694+1G-T) led to retention of the entire intron 19 in the CEP152 mRNA (r.2694G_ins3581, Ile899LeufsX29). (less)
Uncertain significance (Mar 05, 2018)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Seckel syndrome 5 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784550.2 First in ClinVar: Dec 26, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 0-9 years Sex: male Geographic origin: Iran
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30833958, 31980526, 25525159, 21131973, 27219052, 34426522)

Comment:

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000295, PM2). The variant was observed in trans with a pathogenic variant (NM_001194998.1:c.314G>A) as compound heterozygous (3billion dataset, PM3).The variant has been reported as pathogenic (ClinVar ID: VCV000158240.10). 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.Tyr678*) in the CEP152 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP152 are known to be pathogenic (PMID: 21131973). This variant is present in population databases (rs182018947, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with CEP152-related conditions (PMID: 21131973). ClinVar contains an entry for this variant (Variation ID: 158240). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.2034T>G (p.Y678*) alteration, located in exon 16 (coding exon 15) of the CEP152 gene, consists of a T to G substitution at nucleotide position 2034. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 678. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the compound heterozygous state with a second CEP152 alteration in a patient with clinical features of CEP152-related Seckel syndrome (Kalay, 2011). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The stop gained c.2034T>G(p.Tyr678Ter) variant in CEP152 gene has been reported previously in compound heterozygous state in individual(s) affected with Seckel syndrome (Kalay E, et. al., 2011; Fujikura K., 2016). The p.Tyr678Ter variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Signifiance / Likely Pathogenic / Pathogenic (multiple submissions). The nucleotide change c.2034T>G in CEP152 is predicted as conserved by GERP++. This sequence change creates a premature translational stop signal (p.Tyr678Ter) in the CEP152 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CEP152 is a genome maintenance protein disrupted in Seckel syndrome.	Kalay E	Nature genetics	2011	PMID: 21131973
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CEP152	-	-	-	-

Text-mined citations for rs182018947 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001194998.2(CEP152):c.2034T>G (p.Tyr678Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs182018947 ...