8-99717158-ATT-ATTT

Variant names:

• chr8-99717158-A-AT
• rs398124337
• NM_017890.5:c.6530-4dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_017890.5(VPS13B):​c.6530-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,564,658 control chromosomes in the GnomAD database, including 272 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (20 hom., cov: 32)
  • Exomes 𝑓: 0.012 (252 hom.)
• Consequence: VPS13B NM_017890.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.735
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-99717158-A-AT is Benign according to our data. Variant chr8-99717158-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.6530-4dupT		splice_region_variant, intron_variant	Intron 36 of 61	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.6455-4dupT		splice_region_variant, intron_variant	Intron 36 of 61	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.6530-4dupT		splice_region_variant, intron_variant	Intron 36 of 61	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.6455-4dupT		splice_region_variant, intron_variant	Intron 36 of 61	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1350 AN: 151324 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00925

Gnomad ASJ AF: 0.00895

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.0153 AC: 3482 AN: 227226 AF XY: 0.0186

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00951

Gnomad EAS exome AF: 0.000302

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0123 AC: 17321 AN: 1413216 Hom.: 252 Cov.: 30 AF XY: 0.0138 AC XY: 9747 AN XY: 704632

African (AFR) AF: 0.00180 AC: 58 AN: 32286

American (AMR) AF: 0.00504 AC: 222 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 257 AN: 25472

East Asian (EAS) AF: 0.000309 AC: 12 AN: 38828

South Asian (SAS) AF: 0.0635 AC: 5395 AN: 85010

European-Finnish (FIN) AF: 0.0140 AC: 735 AN: 52628

Middle Eastern (MID) AF: 0.0183 AC: 103 AN: 5630

European-Non Finnish (NFE) AF: 0.00913 AC: 9773 AN: 1070822

Other (OTH) AF: 0.0131 AC: 766 AN: 58532

GnomAD4 genome AF: 0.00889 AC: 1347 AN: 151442 Hom.: 20 Cov.: 32 AF XY: 0.0103 AC XY: 762 AN XY: 74004

African (AFR) AF: 0.00160 AC: 66 AN: 41296

American (AMR) AF: 0.00924 AC: 140 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 31 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0712 AC: 341 AN: 4788

European-Finnish (FIN) AF: 0.0143 AC: 150 AN: 10492

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00886 AC: 600 AN: 67754

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00509 Hom.: 0

Bravo AF: 0.00652

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 11, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.6530-4dupT in VPS13B gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.01956 (1930/98690 chrs tested, including 49 homozygotes), predominantly in individuals of South Asian descent (0.068; 1002/14612 chrs tested). The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0025, suggesting that it is likely to be a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Likely Benign/Benign by reputable database/clinical laboratory. Taking together, the variant was classified as Benign. -

Cohen syndrome Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 15, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Jul 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs398124337; hg19: chr8-100729386; COSMIC: COSV100662884; COSMIC: COSV100662884;