rs386834072

Variant names:

• chr8-99134691-AGTATT-A
• rs386834072
• NM_017890.5:c.1269_1273delATTGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152564.5(VPS13B):​c.1269_1273delATTGT​(p.Cys425GlyfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,458,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V423V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS13B NM_152564.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.19
• 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: Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 8-99134691-AGTATT-A is Pathogenic according to our data. Variant chr8-99134691-AGTATT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 56647.Status of the report is criteria_provided_single_submitter, 1 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.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift	Exon 9 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift	Exon 9 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift	Exon 9 of 18	NP_056058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift	Exon 9 of 62	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift	Exon 9 of 62	ENSP00000349685.2
	VPS13B	ENST00000355155.6	TSL:1	n.1269_1273delATTGT		non_coding_transcript_exon	Exon 9 of 28	ENSP00000347281.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458250 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725308

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.00 AC: 0 AN: 85290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110122

Other (OTH) AF: 0.00 AC: 0 AN: 60240

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386834072; hg19: chr8-100146919;