chr8-99778930-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152564.5(VPS13B):c.7678G>A(p.Glu2560Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,934 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 23 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 3.37

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072244406).

BP6

Variant 8-99778930-G-A is Benign according to our data. Variant chr8-99778930-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (464/152280) while in subpopulation NFE AF = 0.00501 (341/68022). AF 95% confidence interval is 0.00457. There are 4 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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.7753G>A	p.Glu2585Lys	missense	Exon 42 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.7678G>A	p.Glu2560Lys	missense	Exon 42 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.7753G>A	p.Glu2585Lys	missense	Exon 42 of 62	ENSP00000351346.2	Q7Z7G8-1
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.7678G>A	p.Glu2560Lys	missense	Exon 42 of 62	ENSP00000349685.2	Q7Z7G8-2
VPS13B	ENST00000682153.1		n.7753G>A		non_coding_transcript_exon	Exon 42 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes

AF:

0.00305

AC:

464

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00326

AC:

818

AN:

250916

AF XY:

0.00330

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00546

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00464

AC:

6789

AN:

1461654

Hom.:

Cov.:

AF XY:

0.00471

AC XY:

3426

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33462

American (AMR)

AF:

0.00273

AC:

122

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00195

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00184

AC:

159

AN:

86248

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00551

AC:

6131

AN:

1111872

Other (OTH)

AF:

0.00440

AC:

266

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

421

842

1263

1684

2105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.00305

AC:

464

AN:

152280

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41566

American (AMR)

AF:

0.00307

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00249

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00501

AC:

341

AN:

68022

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

101

126

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:

0.00397

Hom.:

Bravo

AF:

0.00372

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00322

AC:

391

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00646

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cohen syndrome (6)

not provided (6)

not specified (6)

Inborn genetic diseases (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.025

MetaRNN

Benign

0.0072

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

PhyloP100

3.4

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

REVEL

Benign

0.15

Sift

Benign

0.43

Sift4G

Benign

0.35

Polyphen

0.034

Vest4

0.28

MVP

0.58

MPC

0.14

ClinPred

0.011

GERP RS

3.8

Varity_R

0.061

gMVP

0.34

Mutation Taster

=95/5

disease causing (ClinVar)

(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