rs559590419

Positions:

chr8-99507798-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_017890.5(VPS13B):c.4186C>T(p.Gln1396Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,866 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1396Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

VPS13B
NM_017890.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 1.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-99507798-C-T is Pathogenic according to our data. Variant chr8-99507798-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553132.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.4186C>T	p.Gln1396Ter	stop_gained	28/62	ENST00000358544.7
VPS13B	NM_152564.5 linkuse as main transcript	c.4224+595C>T		intron_variant		ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7 linkuse as main transcript	c.4186C>T	p.Gln1396Ter	stop_gained	28/62	1	NM_017890.5		Q7Z7G8-1
VPS13B	ENST00000357162.7 linkuse as main transcript	c.4224+595C>T		intron_variant		1	NM_152564.5	P1	Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251330

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cohen syndrome

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2023	This sequence change creates a premature translational stop signal (p.Gln1396*) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs559590419, 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: 553132). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.Q1396* in VPS13B (NM_017890.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Q1396* variant is observed in 2/30,612 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been reported previously to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.63

CADD

Benign

DANN

Uncertain

1.0

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;D;N

Vest4

0.94

ClinPred

1.0

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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