rs1554826615

chr8-99511486-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017890.5(VPS13B):c.4684_4685del(p.Glu1562ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B NM_017890.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.48

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-99511486-CAG-C is Pathogenic according to our data. Variant chr8-99511486-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 548466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.4684_4685del	p.Glu1562ArgfsTer7	frameshift_variant	29/62	ENST00000358544.7
VPS13B	NM_152564.5	c.4609_4610del	p.Glu1537ArgfsTer7	frameshift_variant	29/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.4609_4610del	p.Glu1537ArgfsTer7	frameshift_variant	29/62	1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.4684_4685del	p.Glu1562ArgfsTer7	frameshift_variant	29/62	1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 28, 2023	This variant is also known as c.4608_4609del (p.E1537Rfs*7). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 548466). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 31444703). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1562Argfs*7) 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	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1554826615; hg19: chr8-100523714;