rs117148013

Variant names:

Variant summary

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

The NM_152564.5(VPS13B):c.5606C>T(p.Thr1869Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,614,142 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. T1869T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:8

Conservation

PhyloP100: 0.356

Publications

7 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=0.00742206).

BP6

Variant 8-99642196-C-T is Benign according to our data. Variant chr8-99642196-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196918.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. 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.5681C>T	p.Thr1894Met	missense	Exon 34 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.5606C>T	p.Thr1869Met	missense	Exon 34 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.5681C>T	p.Thr1894Met	missense	Exon 34 of 62	ENSP00000351346.2	Q7Z7G8-1
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.5606C>T	p.Thr1869Met	missense	Exon 34 of 62	ENSP00000349685.2	Q7Z7G8-2
VPS13B	ENST00000682153.1		n.5681C>T		non_coding_transcript_exon	Exon 34 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000983

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:

0.00101

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000852

AC:

214

AN:

251256

AF XY:

0.000906

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000999

AC:

1461

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

745

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00181

AC:

156

AN:

86258

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00105

AC:

1170

AN:

1111996

Other (OTH)

AF:

0.000629

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000788

AC:

120

AN:

152290

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41580

American (AMR)

AF:

0.000981

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00166

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68022

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000975

Hom.:

Bravo

AF:

0.000665

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000997

AC:

121

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 (5)

Inborn genetic diseases (1)

not specified (1)

VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.085

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.77

M_CAP

Benign

0.018

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

0.36

PrimateAI

Benign

0.18

PROVEAN

Benign

-1.0

REVEL

Benign

0.041

Sift

Benign

0.30

Sift4G

Benign

0.092

Polyphen

0.013

Vest4

0.18

MVP

0.38

MPC

0.13

ClinPred

0.0014

GERP RS

-1.2

Varity_R

0.024

gMVP

0.31

Mutation Taster

=94/6

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over