rs7833870

Positions:

chr8-99778928-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017890.5(VPS13B):c.7751T>C(p.Val2584Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 1,613,848 control chromosomes in the GnomAD database, including 3,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.088 ( 1051 hom., cov: 32)

Exomes 𝑓: 0.046 ( 2099 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -4.23

Variant links:

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]

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044513345).

BP6

Variant 8-99778928-T-C is Benign according to our data. Variant chr8-99778928-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99778928-T-C is described in Lovd as [Benign]. Variant chr8-99778928-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.7751T>C	p.Val2584Ala	missense_variant	42/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 linkuse as main transcript	c.7676T>C	p.Val2559Ala	missense_variant	42/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.7751T>C	p.Val2584Ala	missense_variant	42/62	1	NM_017890.5	ENSP00000351346		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.7676T>C	p.Val2559Ala	missense_variant	42/62	1	NM_152564.5	ENSP00000349685	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.0878

AC:

13349

AN:

152066

Hom.:

1040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.0472

Gnomad SAS

AF:

0.0220

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0709

GnomAD3 exomes

AF:

0.0514

AC:

12888

AN:

250924

Hom.:

572

AF XY:

0.0466

AC XY:

6316

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.0593

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.0532

Gnomad SAS exome

AF:

0.0222

Gnomad FIN exome

AF:

0.0453

Gnomad NFE exome

AF:

0.0390

Gnomad OTH exome

AF:

0.0421

GnomAD4 exome

AF:

0.0461

AC:

67441

AN:

1461664

Hom.:

2099

Cov.:

AF XY:

0.0445

AC XY:

32343

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.212

Gnomad4 AMR exome

AF:

0.0584

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.0372

Gnomad4 SAS exome

AF:

0.0227

Gnomad4 FIN exome

AF:

0.0423

Gnomad4 NFE exome

AF:

0.0434

Gnomad4 OTH exome

AF:

0.0523

GnomAD4 genome

AF:

0.0880

AC:

13392

AN:

152184

Hom.:

1051

Cov.:

AF XY:

0.0874

AC XY:

6500

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.208

Gnomad4 AMR

AF:

0.0584

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.0469

Gnomad4 SAS

AF:

0.0220

Gnomad4 FIN

AF:

0.0444

Gnomad4 NFE

AF:

0.0416

Gnomad4 OTH

AF:

0.0692

Alfa

AF:

0.0472

Hom.:

769

Bravo

AF:

0.0934

TwinsUK

AF:

0.0348

AC:

129

ALSPAC

AF:

0.0397

AC:

153

ESP6500AA

AF:

0.196

AC:

864

ESP6500EA

AF:

0.0448

AC:

385

ExAC

AF:

0.0537

AC:

6514

Asia WGS

AF:

0.0570

AC:

199

AN:

3478

EpiCase

AF:

0.0387

EpiControl

AF:

0.0352

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2022	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2012	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

DANN

Benign

0.50

DEOGEN2

Benign

0.055

.;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.76

.;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.065

Sift

Benign

0.25

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;B

Vest4

0.026

MPC

0.15

ClinPred

0.0050

GERP RS

-7.9

Varity_R

0.023

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over