6-160245545-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003058.4(SLC22A2):c.958C>T(p.Arg320Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00004 in 1,599,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SLC22A2 NM_003058.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003972
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.169

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06127101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A2	NM_003058.4	c.958C>T	p.Arg320Cys	missense_variant, splice_region_variant	6/11	ENST00000366953.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A2	ENST00000366953.8	c.958C>T	p.Arg320Cys	missense_variant, splice_region_variant	6/11	1	NM_003058.4	P1
SLC22A2	ENST00000366952.1	c.895C>T	p.Arg299Cys	missense_variant, splice_region_variant	8/8	5
SLC22A2	ENST00000491092.1	n.855C>T		splice_region_variant, non_coding_transcript_exon_variant	5/10	5
SLC22A2	ENST00000486916.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000854 AC: 21 AN: 246030 Hom.: 0 AF XY: 0.0000677 AC XY: 9 AN XY: 133016

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000362

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.0000380 AC: 55 AN: 1447230 Hom.: 0 Cov.: 27 AF XY: 0.0000292 AC XY: 21 AN XY: 720382

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000339

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000472

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000227

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74262

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000444 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000551

EpiControl AF: 0.0000597

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.958C>T (p.R320C) alteration is located in exon 6 (coding exon 6) of the SLC22A2 gene. This alteration results from a C to T substitution at nucleotide position 958, causing the arginine (R) at amino acid position 320 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.78
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.023	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	0.54	D;D
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.14
Sift	Benign	0.047	D;T
Sift4G	Uncertain	0.044	D;T
Polyphen		0.0020	B;.
Vest4		0.081
MutPred		0.44		Loss of disorder (P = 0.0109);.;
MVP		0.35
MPC		0.093
ClinPred		0.010	T
GERP RS		-0.38
Varity_R		0.093
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.032
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: rs758136736; hg19: chr6-160666577;