16-56887928-G-T

Variant names:

• chr16-56887928-G-T
• rs36049418
• NM_001126108.2:c.2182G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001126108.2(SLC12A3):​c.2182G>T​(p.Ala728Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,820 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A728T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08835381).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2182G>T	p.Ala728Ser	missense_variant	Exon 18 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2182G>T	p.Ala728Ser	missense_variant	Exon 18 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.2179G>T	p.Ala727Ser	missense_variant	Exon 18 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.2179G>T	p.Ala727Ser	missense_variant	Exon 18 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2182G>T	p.Ala728Ser	missense_variant	Exon 18 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2182G>T	p.Ala728Ser	missense_variant	Exon 18 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2179G>T	p.Ala727Ser	missense_variant	Exon 18 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2179G>T	p.Ala727Ser	missense_variant	Exon 18 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 150994 Hom.: 0 Cov.: 30

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: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458826 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725792

Gnomad4 AFR exome AF: 0.0000299

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 150994 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73674

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.042
DANN	Benign	0.17
DEOGEN2	Benign	0.18	.;.;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.025	.;N;N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.82	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.10
MutPred		0.50		.;Gain of MoRF binding (P = 0.1001);Gain of MoRF binding (P = 0.1001);.;
MVP		0.61
MPC		0.080
ClinPred		0.038	T
GERP RS		-0.68
Varity_R		0.039
gMVP		0.56

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: rs36049418; hg19: chr16-56921840;