rs201963516

chr8-99776893-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_017890.5(VPS13B):c.7441G>A(p.Val2481Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2481A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.838

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07302892).
• BP6: Variant 8-99776893-G-A is Benign according to our data. Variant chr8-99776893-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95865.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.7441G>A	p.Val2481Ile	missense_variant	41/62	ENST00000358544.7
VPS13B	NM_152564.5	c.7366G>A	p.Val2456Ile	missense_variant	41/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.7441G>A	p.Val2481Ile	missense_variant	41/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.7366G>A	p.Val2456Ile	missense_variant	41/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251362 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135846

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727212

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74390

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 14, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 02, 2022

Variant summary: VPS13B c.7441G>A (p.Val2481Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251362 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (0.00017 vs 0.0025), allowing no conclusion about variant significance. c.7441G>A has been reported in the literature as a homozygous genotype in an individual who underwent diagnostic exome sequencing for severe intellectual disability (example, de Ligt_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

VPS13B-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

The VPS13B c.7366G>A variant is predicted to result in the amino acid substitution p.Val2456Ile. This variant, which is referred to as c.7441G>A (p.Val2481Ile) on an alternative transcript (NM_017890), has been reported in the homozygous state in an individual with severe intellectual disability (Table S9, de Ligt et al. 2012. PubMed ID: 23033978). However, several other homozygous variants in other genes were identified in this individual and it is not clear if this variant was contributing to the phenotypes. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 08, 2013

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2017

This alteration is classified as likely 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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	0.0090
Dann	Benign	0.55
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.12	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.57	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0030	B;B
Vest4		0.10
MVP		0.13
MPC		0.098
ClinPred		0.0017	T
GERP RS		-5.7
Varity_R		0.023
gMVP		0.092

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201963516; hg19: chr8-100789121; COSMIC: COSV100660364;