18-8609791-C-T

Variant names:

• chr18-8609791-C-T
• rs752093779
• NM_001025300.3:c.352C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001025300.3(RAB12):​c.352C>T​(p.Pro118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,390,144 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P118R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: RAB12 NM_001025300.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.88
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006830156).
• BS2: High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025300.3. 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
	RAB12	NM_001025300.3	MANE Select	c.352C>T	p.Pro118Ser	missense	Exon 1 of 6	NP_001020471.3	A0A3B3ITT1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB12	ENST00000649141.2	MANE Select	c.352C>T	p.Pro118Ser	missense	Exon 1 of 6	ENSP00000497886.1	A0A3B3ITT1

Frequencies

GnomAD3 genomes AF: 0.000146 AC: 22 AN: 150772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000775 AC: 3 AN: 38714 AF XY: 0.0000902

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00233

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 62 AN: 1239270 Hom.: 0 Cov.: 31 AF XY: 0.0000496 AC XY: 30 AN XY: 605436

African (AFR) AF: 0.000123 AC: 3 AN: 24344

American (AMR) AF: 0.00 AC: 0 AN: 13740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18164

East Asian (EAS) AF: 0.00179 AC: 49 AN: 27406

South Asian (SAS) AF: 0.0000921 AC: 5 AN: 54282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1004780

Other (OTH) AF: 0.0000997 AC: 5 AN: 50144

GnomAD4 genome AF: 0.000146 AC: 22 AN: 150874 Hom.: 0 Cov.: 32 AF XY: 0.0000950 AC XY: 7 AN XY: 73708

African (AFR) AF: 0.000193 AC: 8 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00273 AC: 14 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67542

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000100 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	task-specific movement disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.035
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.15	T
Polyphen		0.056	B
Vest4		0.26
MutPred		0.25		Gain of phosphorylation at P22 (P = 0.011)
MVP		0.47
MPC		1.5
ClinPred		0.089	T
GERP RS		2.1
PromoterAI		-0.0093	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Varity_R		0.14
gMVP		0.57
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs752093779; hg19: chr18-8609789; COSMIC: COSV61398185;