12-193333-G-A

Variant names:

• chr12-193333-G-A
• rs141848384
• NM_001122848.3:c.1474C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001122848.3(SLC6A12):​c.1474C>T​(p.Arg492Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SLC6A12 NM_001122848.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66
• Publications: 5 publications found

Genes affected

SLC6A12 (HGNC:11045): (solute carrier family 6 member 12) Enables monocarboxylic acid transmembrane transporter activity. Involved in monocarboxylic acid transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. Predicted to be active in neuron projection. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255671 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122848.3. 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
	SLC6A12	NM_001122848.3	MANE Select	c.1474C>T	p.Arg492Trp	missense	Exon 14 of 16	NP_001116320.1	P48065
	SLC6A12	NM_001122847.3		c.1474C>T	p.Arg492Trp	missense	Exon 14 of 16	NP_001116319.1	P48065
	SLC6A12	NM_001206931.2		c.1474C>T	p.Arg492Trp	missense	Exon 13 of 15	NP_001193860.1	P48065

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A12	ENST00000684302.1	MANE Select	c.1474C>T	p.Arg492Trp	missense	Exon 14 of 16	ENSP00000508194.1	P48065
	SLC6A12	ENST00000359674.8	TSL:1	c.1474C>T	p.Arg492Trp	missense	Exon 14 of 16	ENSP00000352702.4	P48065
	SLC6A12	ENST00000397296.6	TSL:1	c.1474C>T	p.Arg492Trp	missense	Exon 13 of 15	ENSP00000380464.2	P48065

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 251346 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000347 AC: 507 AN: 1461748 Hom.: 0 Cov.: 30 AF XY: 0.000326 AC XY: 237 AN XY: 727178

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000440 AC: 489 AN: 1111930

Other (OTH) AF: 0.000199 AC: 12 AN: 60390

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74360

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000273

EpiControl AF: 0.000474

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	0.28
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MVP		0.91
ClinPred		0.80	D
GERP RS		4.8
Varity_R		0.75
gMVP		0.58
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141848384; hg19: chr12-302499; COSMIC: COSV100675027; COSMIC: COSV100675027;