rs114120664

Positions:

• chr8-99192993-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000357162.7(VPS13B):​c.2451T>C​(p.His817=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,750 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: VPS13B ENST00000357162.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.833

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-99192993-T-C is Benign according to our data. Variant chr8-99192993-T-C is described in ClinVar as [Benign]. Clinvar id is 262659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99192993-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0059 (898/152268) while in subpopulation AFR AF= 0.0176 (731/41564). AF 95% confidence interval is 0.0165. There are 7 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.2451T>C	p.His817=	synonymous_variant	17/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.2451T>C	p.His817=	synonymous_variant	17/62	ENST00000357162.7	NP_689777.3
VPS13B	NM_015243.3	c.2451T>C	p.His817=	synonymous_variant	17/18		NP_056058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.2451T>C	p.His817=	synonymous_variant	17/62	1	NM_017890.5	ENSP00000351346
VPS13B	ENST00000357162.7	c.2451T>C	p.His817=	synonymous_variant	17/62	1	NM_152564.5	ENSP00000349685	P1

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 896 AN: 152150 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00272 AC: 683 AN: 251226 Hom.: 5 AF XY: 0.00241 AC XY: 327 AN XY: 135804

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00133 AC: 1943 AN: 1461482 Hom.: 8 Cov.: 31 AF XY: 0.00125 AC XY: 911 AN XY: 727048

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000476

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152268 Hom.: 7 Cov.: 32 AF XY: 0.00565 AC XY: 421 AN XY: 74462

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00393 Hom.: 1

Bravo AF: 0.00674

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 10, 2022	- -

Cohen syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.8
DANN	Benign	0.35

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

LitVar

Other links and lift over

dbSNP: rs114120664; hg19: chr8-100205221;