rs34059508

chr6-160154805-G-Achr6-160154805-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003057.3(SLC22A1):c.1393G>A(p.Gly465Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0205 in 1,612,278 control chromosomes in the GnomAD database, including 385 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 0.014 (17 hom., cov: 33)
  • Exomes 𝑓: 0.021 (368 hom.)
• Consequence: SLC22A1 NM_003057.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0138 (2109/152314) while in subpopulation NFE AF= 0.0239 (1625/68028). AF 95% confidence interval is 0.0229. There are 17 homozygotes in gnomad4. There are 959 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A1	NM_003057.3	c.1393G>A	p.Gly465Arg	missense_variant	9/11	ENST00000366963.9
SLC22A1	XM_005267103.3	c.1393G>A	p.Gly465Arg	missense_variant	9/12
SLC22A1	NM_153187.2	c.1386-1170G>A		intron_variant
SLC22A1	XM_006715552.3	c.1386-3711G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A1	ENST00000366963.9	c.1393G>A	p.Gly465Arg	missense_variant	9/11	1	NM_003057.3	P1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2109 AN: 152196 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00857

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.0131 AC: 3291 AN: 250670 Hom.: 36 AF XY: 0.0129 AC XY: 1752 AN XY: 135454

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.00690

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00694

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0212 AC: 30909 AN: 1459964 Hom.: 368 Cov.: 30 AF XY: 0.0207 AC XY: 15029 AN XY: 726386

Gnomad4 AFR exome AF: 0.00365

Gnomad4 AMR exome AF: 0.00760

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.00762

Gnomad4 NFE exome AF: 0.0255

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0138 AC: 2109 AN: 152314 Hom.: 17 Cov.: 33 AF XY: 0.0129 AC XY: 959 AN XY: 74484

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00857

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0212 Hom.: 64

Bravo AF: 0.0137

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0260 AC: 224

ExAC AF: 0.0131 AC: 1587

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0238

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.30
MutPred		0.79		Loss of catalytic residue at V466 (P = 0.0308);Loss of catalytic residue at V466 (P = 0.0308);
MPC		0.65
ClinPred		0.090	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34059508; hg19: chr6-160575837; COSMIC: COSV61454278; COSMIC: COSV61454278;