11-64591618-C-A

Position:

• chr11-64591618-C-A

Variant summary

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

The NM_144585.4(SLC22A12):​c.62C>A​(p.Thr21Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000034 (0 hom.)
• Consequence: SLC22A12 NM_144585.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.331

Genes affected

SLC22A12 (HGNC:17989): (solute carrier family 22 member 12) The protein encoded by this gene is a member of the organic anion transporter (OAT) family, and it acts as a urate transporter to regulate urate levels in blood. This protein is an integral membrane protein primarily found in epithelial cells of the proximal tubule of the kidney. An elevated level of serum urate, hyperuricemia, is associated with increased incidences of gout, and mutations in this gene cause renal hypouricemia type 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

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=0.32978988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A12	NM_144585.4	c.62C>A	p.Thr21Lys	missense_variant	1/10	ENST00000377574.6	NP_653186.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A12	ENST00000377574.6	c.62C>A	p.Thr21Lys	missense_variant	1/10	1	NM_144585.4	ENSP00000366797.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460926 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726800

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.62C>A (p.T21K) alteration is located in exon 1 (coding exon 1) of the SLC22A12 gene. This alteration results from a C to A substitution at nucleotide position 62, causing the threonine (T) at amino acid position 21 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 21 of the SLC22A12 protein (p.Thr21Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC22A12-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Uncertain	0.68	.;D;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.64	.;T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D;N;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.97	D;P;D;.
Vest4		0.35
MutPred		0.68		Gain of ubiquitination at T21 (P = 0.023);Gain of ubiquitination at T21 (P = 0.023);Gain of ubiquitination at T21 (P = 0.023);Gain of ubiquitination at T21 (P = 0.023);
MVP		0.40
MPC		0.42
ClinPred		0.79	D
GERP RS		-5.3
Varity_R		0.25
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1488921348; hg19: chr11-64359090;