6-160245544-C-T

Variant summary

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

The NM_003058.4(SLC22A2):c.959G>A(p.Arg320His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,603,128 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. R320C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: SLC22A2 NM_003058.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001281
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.129

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=0.049759537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A2	NM_003058.4	c.959G>A	p.Arg320His	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.959G>A	p.Arg320His	missense_variant, splice_region_variant	6/11	1	NM_003058.4	P1
SLC22A2	ENST00000366952.1	c.896G>A	p.Arg299His	missense_variant, splice_region_variant	8/8	5
SLC22A2	ENST00000491092.1	n.856G>A		splice_region_variant, non_coding_transcript_exon_variant	5/10	5
SLC22A2	ENST00000486916.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000324 AC: 8 AN: 247190 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000441 AC: 64 AN: 1451162 Hom.: 0 Cov.: 27 AF XY: 0.0000457 AC XY: 33 AN XY: 722008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000480

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74218

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.0000596

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

Mar 06, 2023

The c.959G>A (p.R320H) alteration is located in exon 6 (coding exon 6) of the SLC22A2 gene. This alteration results from a G to A substitution at nucleotide position 959, causing the arginine (R) at amino acid position 320 to be replaced by a histidine (H). 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	0.072
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.023	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.10
Sift	Benign	0.077	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0020	B;.
Vest4		0.093
MutPred		0.37		Loss of MoRF binding (P = 0.0388);.;
MVP		0.49
MPC		0.085
ClinPred		0.059	T
GERP RS		3.1
Varity_R		0.046
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.036
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: rs766844924; hg19: chr6-160666576; COSMIC: COSV65265779; COSMIC: COSV65265779;