NM_017890.5:c.5576C>T

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.5576C>T(p.Ser1859Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,046 control chromosomes in the GnomAD database, including 97 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S1859S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 92 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.212

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017789304).

BP6

Variant 8-99642091-C-T is Benign according to our data. Variant chr8-99642091-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.5576C>T	p.Ser1859Leu	missense_variant	Exon 34 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5 link	c.5501C>T	p.Ser1834Leu	missense_variant	Exon 34 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.5576C>T	p.Ser1859Leu	missense_variant	Exon 34 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7 link	c.5501C>T	p.Ser1834Leu	missense_variant	Exon 34 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0174

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00869

AC:

2178

AN:

250702

AF XY:

0.00622

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00572

GnomAD4 exome

AF:

0.00176

AC:

2580

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1046

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33478

American (AMR)

AF:

0.0539

AC:

2408

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000453

AC:

AN:

39696

South Asian (SAS)

AF:

0.000186

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000405

AC:

AN:

1111990

Other (OTH)

AF:

0.00132

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

190

380

570

760

950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00219

AC:

333

AN:

152252

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41556

American (AMR)

AF:

0.0173

AC:

265

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000712

Hom.:

Bravo

AF:

0.00494

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00707

AC:

858

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 05, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Cohen syndrome

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Oct 11, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Apr 04, 2017

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

0.070

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0

.;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N

PhyloP100

0.21

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.078

Sift

Benign

0.50

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.25

ClinPred

0.0031

GERP RS

0.15

Varity_R

0.028

gMVP

0.22

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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