rs386834091

Positions:

• chr8-99521012-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_017890.5(VPS13B):​c.4820+2T>C variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B NM_017890.5 splice_donor
• Scores: Splicing: ADA: 0.9911
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.00

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 Pathogenic. Variant got 19 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant 8-99521012-T-C is Pathogenic according to our data. Variant chr8-99521012-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 56669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99521012-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.4820+2T>C		splice_donor_variant		ENST00000358544.7
VPS13B	NM_152564.5	c.4745+2T>C		splice_donor_variant		ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.4745+2T>C		splice_donor_variant		1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.4820+2T>C		splice_donor_variant		1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change affects a donor splice site in intron 30 of the VPS13B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Cohen syndrome (PMID: 19006247, 24334764). This variant is also known as IVS30+2T>C. ClinVar contains an entry for this variant (Variation ID: 56669). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 24, 2017	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2019	Variant summary: VPS13B c.4820+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251008 control chromosomes (gnomAD). c.4820+2T>C has been reported in the literature in individuals affected with Cohen Syndrome (CS) (Seifert_2008, El Chehadeh-Djebbar_2013). These data indicate that the variant may be associated with disease. A functional study (Duplomb_2014), suggested that Cohen syndrome is associated with major glycosylation defects, and demonstrated protein N-glycosylation alterations in a serum sample, derived from a compound heterozygous patient carrying the variant of interest. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386834091; hg19: chr8-100533240;