rs28940272

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152564.5(VPS13B):c.8903A>G(p.Asn2968Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,038 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 19 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:12

Conservation

PhyloP100: 7.26

Publications

28 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028394192).

BP6

Variant 8-99820031-A-G is Benign according to our data. Variant chr8-99820031-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2821.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00383 (584/152312) while in subpopulation NFE AF = 0.00557 (379/68010). AF 95% confidence interval is 0.00511. There are 3 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.8978A>G	p.Asn2993Ser	missense	Exon 49 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.8903A>G	p.Asn2968Ser	missense	Exon 49 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.8978A>G	p.Asn2993Ser	missense	Exon 49 of 62	ENSP00000351346.2	Q7Z7G8-1
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.8903A>G	p.Asn2968Ser	missense	Exon 49 of 62	ENSP00000349685.2	Q7Z7G8-2
VPS13B	ENST00000682153.1		n.8978A>G		non_coding_transcript_exon	Exon 49 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes

AF:

0.00384

AC:

584

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00318

AC:

799

AN:

251260

AF XY:

0.00316

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00399

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00493

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00513

AC:

7493

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

3557

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33472

American (AMR)

AF:

0.00385

AC:

172

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00436

AC:

114

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.000475

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000674

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00612

AC:

6801

AN:

1111902

Other (OTH)

AF:

0.00475

AC:

287

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

428

856

1284

1712

2140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00383

AC:

584

AN:

152312

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41582

American (AMR)

AF:

0.00523

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00557

AC:

379

AN:

68010

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

118

148

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:

0.00491

Hom.:

Bravo

AF:

0.00449

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00325

AC:

394

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00485

EpiControl

AF:

0.00498

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cohen syndrome (7)

not provided (3)

not specified (3)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.054

MetaRNN

Benign

0.028

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.1

PhyloP100

7.3

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MVP

0.87

MPC

0.19

ClinPred

0.051

GERP RS

6.1

Varity_R

0.70

gMVP

0.79

Mutation Taster

=73/27

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