rs12208357

Positions:

• chr6-160122116-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003057.3(SLC22A1):​c.181C>T​(p.Arg61Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 1,613,778 control chromosomes in the GnomAD database, including 3,629 homozygotes. In-silico tool predicts 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.048 (230 hom., cov: 33)
  • Exomes 𝑓: 0.064 (3399 hom.)
• Consequence: SLC22A1 NM_003057.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.323

Genes affected

SLC22A1 (HGNC:10963): (solute carrier family 22 member 1) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. This gene is one of three similar cation transporter genes located in a cluster on chromosome 6. The encoded protein contains twelve putative transmembrane domains and is a plasma integral membrane protein. Two transcript variants encoding two different isoforms have been found for this gene, but only the longer variant encodes a functional transporter. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042586923).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A1	NM_003057.3	c.181C>T	p.Arg61Cys	missense_variant	1/11	ENST00000366963.9	NP_003048.1
SLC22A1	NM_153187.2	c.181C>T	p.Arg61Cys	missense_variant	1/10		NP_694857.1
SLC22A1	XM_005267103.3	c.181C>T	p.Arg61Cys	missense_variant	1/12		XP_005267160.1
SLC22A1	XM_006715552.3	c.181C>T	p.Arg61Cys	missense_variant	1/9		XP_006715615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A1	ENST00000366963.9	c.181C>T	p.Arg61Cys	missense_variant	1/11	1	NM_003057.3	ENSP00000355930	P1

Frequencies

GnomAD3 genomes AF: 0.0480 AC: 7306 AN: 152246 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0517 AC: 12989 AN: 251004 Hom.: 459 AF XY: 0.0529 AC XY: 7182 AN XY: 135680

Gnomad AFR exome AF: 0.00998

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0954

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0290

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0761

Gnomad OTH exome AF: 0.0532

GnomAD4 exome AF: 0.0644 AC: 94043 AN: 1461414 Hom.: 3399 Cov.: 32 AF XY: 0.0639 AC XY: 46472 AN XY: 727028

Gnomad4 AFR exome AF: 0.00941

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0964

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0274

Gnomad4 FIN exome AF: 0.0571

Gnomad4 NFE exome AF: 0.0728

Gnomad4 OTH exome AF: 0.0561

GnomAD4 genome AF: 0.0479 AC: 7303 AN: 152364 Hom.: 230 Cov.: 33 AF XY: 0.0451 AC XY: 3361 AN XY: 74504

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.0276

Gnomad4 ASJ AF: 0.0953

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.0590

Gnomad4 NFE AF: 0.0754

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0644 Hom.: 484

Bravo AF: 0.0440

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0729 AC: 281

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.0808 AC: 695

ExAC AF: 0.0524 AC: 6356

Asia WGS AF: 0.0110 AC: 40 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0720

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.13	N
LIST_S2	Pathogenic	0.98	.;D;D;D
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.6	M;M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.6	D;.;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;.;D;D
Sift4G	Uncertain	0.0060	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.36
MPC		0.70
ClinPred		0.049	T
GERP RS		2.7
Varity_R		0.32
gMVP		0.61

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: rs12208357; hg19: chr6-160543148; COSMIC: COSV105878488;