18-8609750-A-C

Variant names:

• chr18-8609750-A-C
• rs998102361
• NM_001025300.3:c.311A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001025300.3(RAB12):​c.311A>C​(p.Gln104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,229,546 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (1 hom.)
• Consequence: RAB12 NM_001025300.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09209964).
• BS2: High AC in GnomAd4 at 57 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.311A>C	p.Gln104Pro	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.311A>C	p.Gln104Pro	missense	Exon 1 of 6	ENSP00000497886.1	A0A3B3ITT1

Frequencies

GnomAD3 genomes AF: 0.000364 AC: 54 AN: 148228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000982

GnomAD4 exome AF: 0.0000601 AC: 65 AN: 1081206 Hom.: 1 Cov.: 30 AF XY: 0.0000446 AC XY: 23 AN XY: 515408

African (AFR) AF: 0.00214 AC: 46 AN: 21476

American (AMR) AF: 0.000141 AC: 1 AN: 7096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12692

East Asian (EAS) AF: 0.00 AC: 0 AN: 23084

South Asian (SAS) AF: 0.0000429 AC: 1 AN: 23308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2842

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 918288

Other (OTH) AF: 0.000404 AC: 17 AN: 42036

GnomAD4 genome AF: 0.000384 AC: 57 AN: 148340 Hom.: 0 Cov.: 32 AF XY: 0.000387 AC XY: 28 AN XY: 72410

African (AFR) AF: 0.00125 AC: 51 AN: 40782

American (AMR) AF: 0.000267 AC: 4 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66740

Other (OTH) AF: 0.000972 AC: 2 AN: 2058

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000484

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.45
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.53	N
REVEL	Benign	0.033
Sift	Benign	0.26	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.31
MPC		1.8
ClinPred		0.22	T
GERP RS		2.4
PromoterAI		0.036	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Varity_R		0.10
gMVP		0.32
Mutation Taster		=91/9	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: rs998102361; hg19: chr18-8609748;