chr8-99481592-C-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.3667-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,612,754 control chromosomes in the GnomAD database, including 2,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 145 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2083 hom. )

Consequence

VPS13B
NM_017890.5 splice_region, intron

Scores

Splicing: ADA: 0.00007806

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.911

Publications

4 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 (BayesDel_noAF=-0.81).

BP6

Variant 8-99481592-C-T is Benign according to our data. Variant chr8-99481592-C-T is described in ClinVar as Benign. ClinVar VariationId is 95848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.3667-7C>T		splice_region_variant, intron_variant	Intron 24 of 61	ENST00000358544.7	NP_060360.3	Q7Z7G8-1
VPS13B	NM_152564.5 link	c.3667-7C>T		splice_region_variant, intron_variant	Intron 24 of 61	ENST00000357162.7	NP_689777.3	Q7Z7G8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 link	c.3667-7C>T		splice_region_variant, intron_variant	Intron 24 of 61	1	NM_017890.5	ENSP00000351346.2		Q7Z7G8-1
VPS13B	ENST00000357162.7 link	c.3667-7C>T		splice_region_variant, intron_variant	Intron 24 of 61	1	NM_152564.5	ENSP00000349685.2		Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5467

AN:

151998

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0506

Gnomad ASJ

AF:

0.0597

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0175

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0525

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0380

AC:

9517

AN:

250768

AF XY:

0.0387

show subpopulations

Gnomad AFR exome

AF:

0.00815

Gnomad AMR exome

AF:

0.0361

Gnomad ASJ exome

AF:

0.0643

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.0553

Gnomad OTH exome

AF:

0.0522

GnomAD4 exome

AF:

0.0489

AC:

71421

AN:

1460638

Hom.:

2083

Cov.:

AF XY:

0.0483

AC XY:

35125

AN XY:

726704

show subpopulations

African (AFR)

AF:

0.0102

AC:

341

AN:

33450

American (AMR)

AF:

0.0384

AC:

1716

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0649

AC:

1695

AN:

26126

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0186

AC:

1604

AN:

86204

European-Finnish (FIN)

AF:

0.0191

AC:

1018

AN:

53190

Middle Eastern (MID)

AF:

0.109

AC:

607

AN:

5576

European-Non Finnish (NFE)

AF:

0.0552

AC:

61366

AN:

1111352

Other (OTH)

AF:

0.0509

AC:

3071

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

3258

6516

9774

13032

16290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2262

4524

6786

9048

11310

<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:

0.0359

AC:

5468

AN:

152116

Hom.:

145

Cov.:

AF XY:

0.0344

AC XY:

2555

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0102

AC:

422

AN:

41520

American (AMR)

AF:

0.0506

AC:

773

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0597

AC:

207

AN:

3466

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0175

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0183

AC:

193

AN:

10572

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0526

AC:

3574

AN:

67974

Other (OTH)

AF:

0.0611

AC:

129

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

265

529

794

1058

1323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0502

Hom.:

133

Bravo

AF:

0.0389

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0595

EpiControl

AF:

0.0602

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cohen syndrome

Benign:7

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Nov 14, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Aug 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.6

(source)

DANN

Benign

0.54

PhyloP100

0.91

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000078

dbscSNV1_RF

Benign

0.026

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over