6-160132354-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003057.3(SLC22A1):c.638G>C(p.Ser213Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC22A1 NM_003057.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.82

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38815305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A1	NM_003057.3	c.638G>C	p.Ser213Thr	missense_variant	3/11	ENST00000366963.9
SLC22A1	NM_153187.2	c.638G>C	p.Ser213Thr	missense_variant	3/10
SLC22A1	XM_005267103.3	c.638G>C	p.Ser213Thr	missense_variant	3/12
SLC22A1	XM_006715552.3	c.638G>C	p.Ser213Thr	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A1	ENST00000366963.9	c.638G>C	p.Ser213Thr	missense_variant	3/11	1	NM_003057.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000813 AC: 2 AN: 246096 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 132908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456806 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Feb 28, 2024

The c.638G>C (p.S213T) alteration is located in exon 3 (coding exon 3) of the SLC22A1 gene. This alteration results from a G to C substitution at nucleotide position 638, causing the serine (S) at amino acid position 213 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.5	L;L;L;L;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.24	T;.;T;T;T
Sift4G	Benign	0.48	T;.;T;T;D
Polyphen		0.13	B;B;P;.;.
Vest4		0.63
MutPred		0.59		Loss of MoRF binding (P = 0.1298);Loss of MoRF binding (P = 0.1298);Loss of MoRF binding (P = 0.1298);Loss of MoRF binding (P = 0.1298);.;
MVP		0.42
MPC		0.56
ClinPred		0.69	D
GERP RS		4.3
Varity_R		0.54
gMVP		0.38

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: rs756046120; hg19: chr6-160553386;