rs7833870

chr8-99778928-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017890.5(VPS13B):c.7751T>C(p.Val2584Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 1,613,848 control chromosomes in the GnomAD database, including 3,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2584L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (1051 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2099 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.23

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 (MetaRNN=0.0044513345).
• BP6: Variant 8-99778928-T-C is Benign according to our data. Variant chr8-99778928-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99778928-T-C is described in Lovd as [Benign]. Variant chr8-99778928-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.7751T>C	p.Val2584Ala	missense_variant	42/62	ENST00000358544.7
VPS13B	NM_152564.5	c.7676T>C	p.Val2559Ala	missense_variant	42/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.7751T>C	p.Val2584Ala	missense_variant	42/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.7676T>C	p.Val2559Ala	missense_variant	42/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.0878 AC: 13349 AN: 152066 Hom.: 1040 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0709

GnomAD3 exomes AF: 0.0514 AC: 12888 AN: 250924 Hom.: 572 AF XY: 0.0466 AC XY: 6316 AN XY: 135594

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0593

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.0532

Gnomad SAS exome AF: 0.0222

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0390

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0461 AC: 67441 AN: 1461664 Hom.: 2099 Cov.: 32 AF XY: 0.0445 AC XY: 32343 AN XY: 727130

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.0584

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.0372

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0434

Gnomad4 OTH exome AF: 0.0523

GnomAD4 genome AF: 0.0880 AC: 13392 AN: 152184 Hom.: 1051 Cov.: 32 AF XY: 0.0874 AC XY: 6500 AN XY: 74412

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0584

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.0469

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0692

Alfa AF: 0.0472 Hom.: 769

Bravo AF: 0.0934

TwinsUK AF: 0.0348 AC: 129

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.196 AC: 864

ESP6500EA AF: 0.0448 AC: 385

ExAC AF: 0.0537 AC: 6514

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.0387

EpiControl AF: 0.0352

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2022	- -

Cohen syndrome Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.0010
Dann	Benign	0.50
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.065
Sift	Benign	0.25	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;B
Vest4		0.026
MPC		0.15
ClinPred		0.0050	T
GERP RS		-7.9
Varity_R		0.023
gMVP		0.11

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: rs7833870; hg19: chr8-100791156; COSMIC: COSV62144753; COSMIC: COSV62144753;