18-8609762-G-C

Variant names:

• chr18-8609762-G-C
• rs1185791654
• NM_001025300.3:c.323G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001025300.3(RAB12):​c.323G>C​(p.Gly108Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,114,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RAB12 NM_001025300.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

RAB12 (HGNC:31332): (RAB12, member RAS oncogene family) Enables GDP binding activity. Predicted to be involved in several processes, including cellular response to insulin stimulus; endosome to lysosome transport; and secretion by cell. Predicted to act upstream of or within cellular response to interferon-gamma. Predicted to be located in lysosome; phagocytic vesicle; and recycling endosome membrane. Predicted to be active in Golgi apparatus; cytoplasmic vesicle; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07422218).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB12	NM_001025300.3	c.323G>C	p.Gly108Ala	missense_variant	Exon 1 of 6	ENST00000649141.2	NP_001020471.3
RAB12	XR_001753165.2	n.326G>C		non_coding_transcript_exon_variant	Exon 1 of 4
RAB12	XR_001753166.2	n.326G>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB12	ENST00000649141.2	c.323G>C	p.Gly108Ala	missense_variant	Exon 1 of 6		NM_001025300.3	ENSP00000497886.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000126 AC: 14 AN: 1114224 Hom.: 0 Cov.: 30 AF XY: 0.0000131 AC XY: 7 AN XY: 533512

Gnomad4 AFR exome AF: 0.0000450

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000128

Gnomad4 OTH exome AF: 0.0000227

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>C (p.G12A) alteration is located in exon 1 (coding exon 1) of the RAB12 gene. This alteration results from a G to C substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by an alanine (A). 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	Benign	0.077
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.026	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.49	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	.;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.10	.;N
REVEL	Benign	0.078
Sift	Benign	1.0	.;T
Sift4G	Benign	0.60	.;T
Polyphen		0.0	.;B
Vest4		0.17
MutPred		0.17		.;Loss of loop (P = 0.0128);
MVP		0.30
MPC		1.6
ClinPred		0.033	T
GERP RS		1.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.6
Varity_R		0.030
gMVP		0.24

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: rs1185791654; hg19: chr18-8609760;