NM_017890.5:c.6491A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017890.5(VPS13B):c.6491A>G(p.Asn2164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000909 in 1,613,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N2164N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

VPS13B
NM_017890.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:7

Conservation

PhyloP100: -2.02

Publications

5 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: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007905126).

BP6

Variant 8-99699894-A-G is Benign according to our data. Variant chr8-99699894-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196985.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.6491A>G	p.Asn2164Ser	missense	Exon 36 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.6416A>G	p.Asn2139Ser	missense	Exon 36 of 62	NP_689777.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.6491A>G	p.Asn2164Ser	missense	Exon 36 of 62	ENSP00000351346.2	Q7Z7G8-1
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.6416A>G	p.Asn2139Ser	missense	Exon 36 of 62	ENSP00000349685.2	Q7Z7G8-2
VPS13B	ENST00000682153.1		n.6491A>G		non_coding_transcript_exon	Exon 36 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000822

AC:

206

AN:

250482

AF XY:

0.000863

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.000990

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.000930

AC:

1360

AN:

1461676

Hom.:

Cov.:

AF XY:

0.000950

AC XY:

691

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.000157

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00175

AC:

151

AN:

86216

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000975

AC:

1084

AN:

1111964

Other (OTH)

AF:

0.000497

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000703

AC:

107

AN:

152260

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41566

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68010

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000902

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cohen syndrome (9)

not provided (4)

Inborn genetic diseases (1)

not specified (1)

VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.044

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.64

M_CAP

Benign

0.012

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.97

PhyloP100

-2.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.17

REVEL

Benign

0.061

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.073

MVP

0.28

MPC

0.096

ClinPred

0.012

GERP RS

-7.7

Varity_R

0.032

gMVP

0.075

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over