rs8177517

Positions:

• chr6-160242388-T-C
• chr6-160242388-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003058.4(SLC22A2):​c.1294A>G​(p.Lys432Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K432Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC22A2 NM_003058.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92

Genes affected

SLC22A2 (HGNC:10966): (solute carrier family 22 member 2) 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. It is found primarily in the kidney, where it may mediate the first step in cation reabsorption. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A2	NM_003058.4	c.1294A>G	p.Lys432Glu	missense_variant	8/11	ENST00000366953.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A2	ENST00000366953.8	c.1294A>G	p.Lys432Glu	missense_variant	8/11	1	NM_003058.4	P1
SLC22A2	ENST00000486916.5	n.333A>G		non_coding_transcript_exon_variant	3/6	3
SLC22A2	ENST00000491092.1	n.1191A>G		non_coding_transcript_exon_variant	7/10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251024 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439026 Hom.: 0 Cov.: 26 AF XY: 0.00000279 AC XY: 2 AN XY: 717526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.047
Eigen_PC	Benign	0.014
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.72	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.50	T
Polyphen		0.49	P
Vest4		0.36
MutPred		0.63		Loss of ubiquitination at K432 (P = 0.0174);
MVP		0.57
MPC		0.22
ClinPred		0.75	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.87

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: rs8177517; hg19: chr6-160663420;