rs180177371

chr8-99853767-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017890.5(VPS13B):c.10456_10457del(p.Leu3487ProfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VPS13B NM_017890.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.30

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-99853767-CAG-C is Pathogenic according to our data. Variant chr8-99853767-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99853767-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.10456_10457del	p.Leu3487ProfsTer24	frameshift_variant	56/62	ENST00000358544.7
VPS13B	NM_152564.5	c.10381_10382del	p.Leu3462ProfsTer24	frameshift_variant	56/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.10381_10382del	p.Leu3462ProfsTer24	frameshift_variant	56/62	1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.10456_10457del	p.Leu3487ProfsTer24	frameshift_variant	56/62	1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461894 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 13, 2022	This variant is present in population databases (rs746694263, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 68080). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 16648375). This sequence change creates a premature translational stop signal (p.Leu3487Profs*24) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2022	Variant summary: VPS13B c.10456_10457delAG (p.Leu3487ProfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251474 control chromosomes. c.10456_10457delAG has been reported in the literature in at least one individual affected with Cohen Syndrome. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2016	- -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

SNPedia

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs180177371; hg19: chr8-100865995;