8-99766874-C-T

Position:

chr8-99766874-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152564.5(VPS13B):c.7151C>T(p.Pro2384Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P2384P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

VPS13B
NM_152564.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.35

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 links:

VPS13B (HGNC:):

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.7226C>T	p.Pro2409Leu	missense_variant	40/62	ENST00000358544.7	NP_060360.3	Q7Z7G8-1
VPS13B	NM_152564.5 linkuse as main transcript	c.7151C>T	p.Pro2384Leu	missense_variant	40/62	ENST00000357162.7	NP_689777.3	Q7Z7G8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.7226C>T	p.Pro2409Leu	missense_variant	40/62	1	NM_017890.5	ENSP00000351346.2		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.7151C>T	p.Pro2384Leu	missense_variant	40/62	1	NM_152564.5	ENSP00000349685.2		Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251102

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000835

AC:

122

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cohen syndrome

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2409 of the VPS13B protein (p.Pro2409Leu). This variant is present in population databases (rs183874686, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 212580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS13B protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 12, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2018

The p.P2409L variant (also known as c.7226C>T), located in coding exon 39 of the VPS13B gene, results from a C to T substitution at nucleotide position 7226. The proline at codon 2409 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

VPS13B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The VPS13B c.7151C>T variant is predicted to result in the amino acid substitution p.Pro2384Leu. To our knowledge, this variant has not been reported in the literature in any individuals diagnosed with Cohen syndrome. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.056

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.85

MVP

0.93

MPC

0.53

ClinPred

0.88

GERP RS

6.0

Varity_R

0.64

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over