VCV002975389.1 - ClinVar

NM_006031.6(PCNT):c.8680_8689del (p.Ser2894fs)

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.

(2)

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_006031.6(PCNT):c.8680_8689del (p.Ser2894fs)

Variation ID: 2975389 Accession: VCV002975389.1

Type and length

Deletion, 10 bp

Location

Cytogenetic: 21q22.3 21: 46432139-46432148 (GRCh38) [ NCBI UCSC ] 21: 47852053-47852062 (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	Feb 29, 2024	Jun 29, 2024	Jun 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006031.6:c.8680_8689del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006022.3:p.Ser2894fs	frameshift
NM_001315529.2:c.8160+166_8160+175del		intron variant
NC_000021.9:g.46432144_46432153del
NC_000021.8:g.47852058_47852067del
NG_008961.2:g.113023_113032del

... more HGVS ... less HGVS

Protein change

S2894fs

Other names

Canonical SPDI

NC_000021.9:46432138:GGAGGAGCGCGGAGG:GGAGG

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.

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

Links

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.
PCNT		-	-	GRCh38 GRCh37	3603	3779

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 provided	Pathogenic (1)	criteria provided, single submitter	Apr 16, 2023	RCV003830995.2
Microcephalic osteodysplastic primordial dwarfism type II	Likely pathogenic (1)	criteria provided, single submitter	Jun 16, 2024	RCV004577930.1

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 (Apr 16, 2023)	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: SCV004633416.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 18174396‚ 22821869 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PCNT-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PCNT-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser2894Profs*24) in the PCNT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCNT are known to be pathogenic (PMID: 18174396, 22821869). (less)
Likely pathogenic (Jun 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephalic osteodysplastic primordial dwarfism type II (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genomics, Clalit Research Institute, Clalit Health Care Accession: SCV005061581.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Comment: Frequency: The variant is rare, observed in 1 alleles out of 250,104 (0%) in the gnomAD reference population dataset. Variant type: Null variant (frameshift indel) … (more) Frequency: The variant is rare, observed in 1 alleles out of 250,104 (0%) in the gnomAD reference population dataset. Variant type: Null variant (frameshift indel) in a gene where loss of function is a known mechanism of disease. Predicted to undergo NMD. Clinical evidence: This variant has previously been described in ClinVar (VCV2975389) with the following classifications: P (1). PVS1,PM2_supporting (less) Clinical Features: Diabetes mellitus (present) Age: 50-59 years Ethnicity/Population group: Arab muslim

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PCNT-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser2894Profs*24) in the PCNT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCNT are known to be pathogenic (PMID: 18174396, 22821869).

Comment:

Frequency: The variant is rare, observed in 1 alleles out of 250,104 (0%) in the gnomAD reference population dataset. Variant type: Null variant (frameshift indel) in a gene where loss of function is a known mechanism of disease. Predicted to undergo NMD. Clinical evidence: This variant has previously been described in ClinVar (VCV2975389) with the following classifications: P (1). PVS1,PM2_supporting

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
Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations.	Bober MB	American journal of medical genetics. Part A	2012	PMID: 22821869
Mutations in the pericentrin (PCNT) gene cause primordial dwarfism.	Rauch A	Science (New York, N.Y.)	2008	PMID: 18174396

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_006031.6(PCNT):c.8680_8689del (p.Ser2894fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...