17-42128777-A-C

Position:

• chr17-42128777-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000346213.9(RAB5C):​c.190T>G​(p.Cys64Gly) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAB5C ENST00000346213.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

Genes affected

RAB5C (HGNC:9785): (RAB5C, member RAS oncogene family) Members of the Rab protein family are small GTPases of the Ras superfamily that are thought to ensure fidelity in the process of docking and/or fusion of vesicles with their correct acceptor compartment (Han et al., 1996 [PubMed 8646882]).[supplied by OMIM, Nov 2010]

ENSG00000267261 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB5C	NM_004583.4	c.190T>G	p.Cys64Gly	missense_variant	3/6	ENST00000346213.9	NP_004574.2
RAB5C	NM_001252039.2	c.289T>G	p.Cys97Gly	missense_variant	4/7		NP_001238968.1
RAB5C	NM_201434.3	c.190T>G	p.Cys64Gly	missense_variant	4/7		NP_958842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB5C	ENST00000346213.9	c.190T>G	p.Cys64Gly	missense_variant	3/6	1	NM_004583.4	ENSP00000345689.5
ENSG00000267261	ENST00000592574.1	c.190T>G	p.Cys64Gly	missense_variant	3/8	5		ENSP00000468367.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The c.190T>G (p.C64G) alteration is located in exon 4 (coding exon 2) of the RAB5C gene. This alteration results from a T to G substitution at nucleotide position 190, causing the cysteine (C) at amino acid position 64 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Benign	0.95
DEOGEN2	Uncertain	0.51	.;D;D;.;D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.42	.;N;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.6	.;D;D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.093	.;T;T;D;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T;.;.
Polyphen		0.98	.;D;D;.;.;.;.
Vest4		0.86, 0.85, 0.84
MutPred		0.39		Loss of stability (P = 0.0799);Loss of stability (P = 0.0799);Loss of stability (P = 0.0799);.;Loss of stability (P = 0.0799);Loss of stability (P = 0.0799);Loss of stability (P = 0.0799);
MVP		0.76
MPC		0.73
ClinPred		0.86	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40280795;