8-99766969-AGG-AATGGAGC

Position:

• chr8-99766969-AGG-AATGGAGC

Variant summary

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

The NM_017890.5(VPS13B):​c.7322_7322+1delinsATGGAGC variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S2441S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VPS13B NM_017890.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.02

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 +-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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 8-99766970-GG-ATGGAGC is Pathogenic according to our data. Variant chr8-99766970-GG-ATGGAGC is described in ClinVar as [Pathogenic]. Clinvar id is 68091.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.7322_7322+1delinsATGGAGC		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	40/62	ENST00000358544.7
VPS13B	NM_152564.5	c.7247_7247+1delinsATGGAGC		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	40/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.7247_7247+1delinsATGGAGC		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	40/62	1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.7322_7322+1delinsATGGAGC		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	40/62	1	NM_017890.5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

SNPedia

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177367; hg19: chr8-100779198;