rs61753724

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017890.5(VPS13B):c.7038A>G(p.Val2346Val) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.618

Publications

9 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 -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 VariationId is 95863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.7038A>G	p.Val2346Val	synonymous_variant	Exon 39 of 62	ENST00000358544.7	NP_060360.3	Q7Z7G8-1
VPS13B	NM_152564.5 link	c.6963A>G	p.Val2321Val	synonymous_variant	Exon 39 of 62	ENST00000357162.7	NP_689777.3	Q7Z7G8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 link	c.7038A>G	p.Val2346Val	synonymous_variant	Exon 39 of 62	1	NM_017890.5	ENSP00000351346.2		Q7Z7G8-1
VPS13B	ENST00000357162.7 link	c.6963A>G	p.Val2321Val	synonymous_variant	Exon 39 of 62	1	NM_152564.5	ENSP00000349685.2		Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.0686

AC:

10428

AN:

152056

Hom.:

534

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0474

AC:

11903

AN:

251248

AF XY:

0.0441

show subpopulations

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 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.:

AF XY:

0.0431

AC XY:

31322

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.141

AC:

4730

AN:

33474

American (AMR)

AF:

0.0548

AC:

2450

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

479

AN:

26130

East Asian (EAS)

AF:

0.0449

AC:

1783

AN:

39670

South Asian (SAS)

AF:

0.0231

AC:

1991

AN:

86254

European-Finnish (FIN)

AF:

0.0423

AC:

2259

AN:

53414

Middle Eastern (MID)

AF:

0.0198

AC:

114

AN:

5766

European-Non Finnish (NFE)

AF:

0.0434

AC:

48307

AN:

1111914

Other (OTH)

AF:

0.0471

AC:

2842

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

3449

6898

10347

13796

17245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1928

3856

5784

7712

9640

<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:

0.0687

AC:

10457

AN:

152174

Hom.:

537

Cov.:

AF XY:

0.0688

AC XY:

5120

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.139

AC:

5787

AN:

41506

American (AMR)

AF:

0.0503

AC:

769

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3464

East Asian (EAS)

AF:

0.0565

AC:

293

AN:

5182

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4818

European-Finnish (FIN)

AF:

0.0445

AC:

472

AN:

10604

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2826

AN:

67992

Other (OTH)

AF:

0.0569

AC:

120

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

478

957

1435

1914

2392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0566

Hom.:

145

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:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 16, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cohen syndrome

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 02, 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

BayesDel_noAF

Benign

-0.46

CADD

Benign

5.5

(source)

DANN

Benign

0.74

PhyloP100

0.62

Mutation Taster

=97/3

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