rs140095832

Positions:

• chr8-99821393-G-C
• chr8-99821393-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017890.5(VPS13B):​c.9169G>C​(p.Asp3057His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3057Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.70

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3520562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.9169G>C	p.Asp3057His	missense_variant	50/62	ENST00000358544.7
VPS13B	NM_152564.5	c.9094G>C	p.Asp3032His	missense_variant	50/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.9169G>C	p.Asp3057His	missense_variant	50/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.9094G>C	p.Asp3032His	missense_variant	50/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.97	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.85	P;D
Vest4		0.33
MutPred		0.21		.;Loss of ubiquitination at K3054 (P = 0.0261);
MVP		0.87
MPC		0.54
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.38

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: rs140095832; hg19: chr8-100833621;