rs61753724

chr8-99720960-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017890.5(VPS13B):c.7038A>G(p.Val2346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,613,908 control chromosomes in the GnomAD database, including 2,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (537 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1688 hom.)
• Consequence: VPS13B NM_017890.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.618

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-99720960-A-G is Benign according to our data. Variant chr8-99720960-A-G is described in ClinVar as [Benign]. Clinvar id is 95863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99720960-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.618 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.7038A>G	p.Val2346=	synonymous_variant	39/62	ENST00000358544.7
VPS13B	NM_152564.5	c.6963A>G	p.Val2321=	synonymous_variant	39/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.7038A>G	p.Val2346=	synonymous_variant	39/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.6963A>G	p.Val2321=	synonymous_variant	39/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10428 AN: 152056 Hom.: 534 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0566

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0580

GnomAD3 exomes AF: 0.0474 AC: 11903 AN: 251248 Hom.: 404 AF XY: 0.0441 AC XY: 5982 AN XY: 135790

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0560

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.0633

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0444 AC: 64955 AN: 1461734 Hom.: 1688 Cov.: 32 AF XY: 0.0431 AC XY: 31322 AN XY: 727168

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.0231

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0434

Gnomad4 OTH exome AF: 0.0471

GnomAD4 genome AF: 0.0687 AC: 10457 AN: 152174 Hom.: 537 Cov.: 32 AF XY: 0.0688 AC XY: 5120 AN XY: 74394

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.0503

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.0565

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0445

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0569

Alfa AF: 0.0555 Hom.: 138

Bravo AF: 0.0727

Asia WGS AF: 0.0560 AC: 197 AN: 3476

EpiCase AF: 0.0386

EpiControl AF: 0.0348

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2022	- -

Cohen syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	5.5
Dann	Benign	0.74

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: rs61753724; hg19: chr8-100733188; COSMIC: COSV62136791;