rs120074149

Positions:

• chr8-99717219-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000357162.7(VPS13B):​c.6503T>G​(p.Leu2168Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B ENST00000357162.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.99

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 8-99717219-T-G is Pathogenic according to our data. Variant chr8-99717219-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2819.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-99717219-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.6578T>G	p.Leu2193Arg	missense_variant	37/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.6503T>G	p.Leu2168Arg	missense_variant	37/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.6578T>G	p.Leu2193Arg	missense_variant	37/62	1	NM_017890.5	ENSP00000351346
VPS13B	ENST00000357162.7	c.6503T>G	p.Leu2168Arg	missense_variant	37/62	1	NM_152564.5	ENSP00000349685	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cohen syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.011	D
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	0.97	A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;P
Vest4		0.63
MutPred		0.88		.;Loss of stability (P = 0.0143);
MVP		0.86
MPC		0.55
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs120074149; hg19: chr8-100729447;