rs7833870

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2584L) has been classified 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

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

Cohen syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 95866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.7751T>C	p.Val2584Ala	missense_variant	Exon 42 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 link	c.7676T>C	p.Val2559Ala	missense_variant	Exon 42 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 link	c.7751T>C	p.Val2584Ala	missense_variant	Exon 42 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7 link	c.7676T>C	p.Val2559Ala	missense_variant	Exon 42 of 62	1	NM_152564.5	ENSP00000349685.2

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

GnomAD2 exomes

AF:

0.0514

AC:

12888

AN:

250924

AF XY:

0.0466

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 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

African (AFR)

AF:

0.212

AC:

7089

AN:

33464

American (AMR)

AF:

0.0584

AC:

2610

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

481

AN:

26130

East Asian (EAS)

AF:

0.0372

AC:

1475

AN:

39672

South Asian (SAS)

AF:

0.0227

AC:

1956

AN:

86258

European-Finnish (FIN)

AF:

0.0423

AC:

2259

AN:

53418

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5764

European-Non Finnish (NFE)

AF:

0.0434

AC:

48287

AN:

1111872

Other (OTH)

AF:

0.0523

AC:

3159

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

4026

8052

12077

16103

20129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1962

3924

5886

7848

9810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0880

AC:

13392

AN:

152184

Hom.:

1051

Cov.:

AF XY:

0.0874

AC XY:

6500

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.208

AC:

8613

AN:

41506

American (AMR)

AF:

0.0584

AC:

892

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3472

East Asian (EAS)

AF:

0.0469

AC:

243

AN:

5176

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4820

European-Finnish (FIN)

AF:

0.0444

AC:

471

AN:

10606

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2830

AN:

68002

Other (OTH)

AF:

0.0692

AC:

146

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

611

1222

1834

2445

3056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0523

Hom.:

1828

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

Nov 14, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Dec 16, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cohen syndrome

Benign:5

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Benign:1

Apr 18, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

-4.2

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over