chr12-191211-G-A

Position:

• chr12-191211-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001122848.3(SLC6A12):​c.1702C>T​(p.Arg568Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,114,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC6A12 NM_001122848.3 missense, splice_region
• Scores: Splicing: ADA: 0.9878
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A12	NM_001122848.3	c.1702C>T	p.Arg568Cys	missense_variant, splice_region_variant	16/16	ENST00000684302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A12	ENST00000684302.1	c.1702C>T	p.Arg568Cys	missense_variant, splice_region_variant	16/16		NM_001122848.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000108 AC: 12 AN: 1114384 Hom.: 0 Cov.: 30 AF XY: 0.0000114 AC XY: 6 AN XY: 528272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000369

Gnomad4 SAS exome AF: 0.0000846

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000862

Gnomad4 OTH exome AF: 0.0000223

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000103 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;.;.;.
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.97	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.83	P;P;P;P
Vest4		0.53
MutPred		0.78		Gain of catalytic residue at L569 (P = 0.0194);Gain of catalytic residue at L569 (P = 0.0194);Gain of catalytic residue at L569 (P = 0.0194);Gain of catalytic residue at L569 (P = 0.0194);
MVP		0.88
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.62
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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: rs748353817; hg19: chr12-300377; COSMIC: COSV62885474; COSMIC: COSV62885474;