rs180177367

Variant names:

• chr8-99766970-GG-ATGGAGC
• rs180177367
• NM_017890.5:c.7322_7322+1delGGinsATGGAGC

Your query was ambiguous. Multiple possible variants found:

• chr8-99766969-AGG-AATGGAGC
• chr8-99766969-AGG-AG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_152564.5(VPS13B):​c.7247_7247+1delGGinsATGGAGC​(p.Ser2416delinsAsnGly???) variant causes a splice donor, missense, splice region, 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2416C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VPS13B NM_152564.5 splice_donor, missense, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.02
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 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
• PP5: Variant 8-99766970-GG-ATGGAGC is Pathogenic according to our data. Variant chr8-99766970-GG-ATGGAGC is described in ClinVar as Pathogenic. ClinVar VariationId is 68091.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.7322_7322+1delGGinsATGGAGC	p.Ser2441delinsAsnGly???	splice_donor missense splice_region intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.7247_7247+1delGGinsATGGAGC	p.Ser2416delinsAsnGly???	splice_donor missense splice_region intron	N/A	NP_689777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.7322_7322+1delGGinsATGGAGC	p.Ser2441delinsAsnGly???	splice_donor missense splice_region intron	N/A	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.7247_7247+1delGGinsATGGAGC	p.Ser2416delinsAsnGly???	splice_donor missense splice_region intron	N/A	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000683334.1		n.*3004_*3004+1delGGinsATGGAGC		splice_region non_coding_transcript_exon	Exon 39 of 61	ENSP00000507369.1	A0A804HJ62

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

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=1/199	disease causing

Splicing

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

Other links and lift over

dbSNP: rs180177367; hg19: chr8-100779198;