rs587777381

chr8-99642499-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_017890.5(VPS13B):c.5983+2dup variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,402 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS13B NM_017890.5 splice_donor
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.75

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 12 ACMG points.

• PVS1: Splicing 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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-99642499-G-GT is Pathogenic according to our data. Variant chr8-99642499-G-GT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132794.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.5983+2dup		splice_donor_variant		ENST00000358544.7
VPS13B	NM_152564.5	c.5908+2dup		splice_donor_variant		ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.5908+2dup		splice_donor_variant		1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.5983+2dup		splice_donor_variant		1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458402 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725532

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 07, 2023	This variant has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 24311531). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that this variant alters VPS13B gene expression (PMID: 24311531). ClinVar contains an entry for this variant (Variation ID: 132794). This variant is also known as IVS34+2T_+3AinsT. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 34 of the VPS13B gene. It does not directly change the encoded amino acid sequence of the VPS13B protein. It affects a nucleotide within the consensus splice site. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 09, 2022	_x000D_ Criteria applied: PVS1, PM3_STR, PM2_SUP, PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777381; hg19: chr8-100654727;