12-209959-A-G

Variant names:

• chr12-209959-A-G
• rs557881
• NM_001122848.3:c.28T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001122848.3(SLC6A12):​c.28T>C​(p.Cys10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,410 control chromosomes in the GnomAD database, including 224,172 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C10Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.56 (24537 hom., cov: 32)
  • Exomes 𝑓: 0.52 (199635 hom.)
• Consequence: SLC6A12 NM_001122848.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 34 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.607937E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A12	NM_001122848.3	c.28T>C	p.Cys10Arg	missense_variant	Exon 3 of 16	ENST00000684302.1	NP_001116320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A12	ENST00000684302.1	c.28T>C	p.Cys10Arg	missense_variant	Exon 3 of 16		NM_001122848.3	ENSP00000508194.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85164 AN: 151886 Hom.: 24488 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.561

GnomAD2 exomes AF: 0.515 AC: 129294 AN: 251198 AF XY: 0.517

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.619

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.520 AC: 759700 AN: 1461406 Hom.: 199635 Cov.: 47 AF XY: 0.521 AC XY: 379003 AN XY: 727032

African (AFR) AF: 0.709 AC: 23739 AN: 33474

American (AMR) AF: 0.426 AC: 19032 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 16084 AN: 26136

East Asian (EAS) AF: 0.335 AC: 13306 AN: 39698

South Asian (SAS) AF: 0.562 AC: 48490 AN: 86246

European-Finnish (FIN) AF: 0.530 AC: 28296 AN: 53406

Middle Eastern (MID) AF: 0.609 AC: 3512 AN: 5764

European-Non Finnish (NFE) AF: 0.518 AC: 575505 AN: 1111592

Other (OTH) AF: 0.526 AC: 31736 AN: 60376

GnomAD4 genome AF: 0.561 AC: 85266 AN: 152004 Hom.: 24537 Cov.: 32 AF XY: 0.556 AC XY: 41329 AN XY: 74276

African (AFR) AF: 0.701 AC: 29079 AN: 41486

American (AMR) AF: 0.469 AC: 7173 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2144 AN: 3468

East Asian (EAS) AF: 0.336 AC: 1730 AN: 5154

South Asian (SAS) AF: 0.561 AC: 2706 AN: 4822

European-Finnish (FIN) AF: 0.511 AC: 5395 AN: 10554

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35156 AN: 67924

Other (OTH) AF: 0.561 AC: 1185 AN: 2112

Alfa AF: 0.531 Hom.: 50083

Bravo AF: 0.564

TwinsUK AF: 0.520 AC: 1927

ALSPAC AF: 0.525 AC: 2025

ESP6500AA AF: 0.702 AC: 3094

ESP6500EA AF: 0.529 AC: 4550

ExAC AF: 0.524 AC: 63567

Asia WGS AF: 0.445 AC: 1548 AN: 3478

EpiCase AF: 0.531

EpiControl AF: 0.526

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.51
DEOGEN2	Benign	0.017	T;T;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.10	T;.;.;.;T;T
MetaRNN	Benign	0.0000036	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;N;N;N;.;.
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.51	N;N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.52	T;T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T
Vest4		0.014
ClinPred		0.0018	T
GERP RS		2.8
Varity_R		0.052
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs557881; hg19: chr12-319125; COSMIC: COSV62885336; COSMIC: COSV62885336;