chr12-209959-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C10S) 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

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

Verdict is Benign. Variant got -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

GnomAD3 exomes AF: 0.515 AC: 129294 AN: 251198 Hom.: 34191 AF XY: 0.517 AC XY: 70198 AN XY: 135790

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 SAS exome AF: 0.563

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

Gnomad4 AFR exome AF: 0.709

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.615

Gnomad4 EAS exome AF: 0.335

Gnomad4 SAS exome AF: 0.562

Gnomad4 FIN exome AF: 0.530

Gnomad4 NFE exome AF: 0.518

Gnomad4 OTH exome AF: 0.526

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

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.618

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.511

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.561

Alfa AF: 0.528 Hom.: 31723

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;.;.
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
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.014
ClinPred		0.0018	T
GERP RS		2.8
Varity_R		0.052
gMVP		0.18

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