16-56865261-C-T

Variant names:

• chr16-56865261-C-T
• rs111313053
• NM_001126108.2:c.26C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001126108.2(SLC12A3):​c.26C>T​(p.Thr9Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.624

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 134) in uniprot entity S12A3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05191648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.26C>T	p.Thr9Met	missense_variant	Exon 1 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249750 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135292

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461458 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727040

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74384

Gnomad4 AFR AF: 0.0000482

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.4
DANN	Benign	0.65
DEOGEN2	Benign	0.19	.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.14
MVP		0.35
MPC		0.090
ClinPred		0.054	T
GERP RS		-6.1
Varity_R		0.021
gMVP		0.42

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: rs111313053; hg19: chr16-56899173; COSMIC: COSV52633943;