rs121909384

Positions:

• chr16-56885328-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001126108.2(SLC12A3):​c.1889G>T​(p.Gly630Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.76

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772
• PP5: Variant 16-56885328-G-T is Pathogenic according to our data. Variant chr16-56885328-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8594.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1889G>T	p.Gly630Val	missense_variant	15/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1889G>T	p.Gly630Val	missense_variant	15/26		NP_000330.3
SLC12A3	NM_001126107.2	c.1886G>T	p.Gly629Val	missense_variant	15/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1886G>T	p.Gly629Val	missense_variant	15/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1889G>T	p.Gly630Val	missense_variant	15/26	1	NM_001126108.2	ENSP00000456149	A1
SLC12A3	ENST00000438926.6	c.1889G>T	p.Gly630Val	missense_variant	15/26	1		ENSP00000402152	A1
SLC12A3	ENST00000566786.5	c.1886G>T	p.Gly629Val	missense_variant	15/26	1		ENSP00000457552	P4
SLC12A3	ENST00000262502.5	c.1886G>T	p.Gly629Val	missense_variant	15/26	5		ENSP00000262502	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1403062 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692430

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	.;.;D;D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	.;L;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.22
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.10	B;B;D;.
Vest4		0.87
MutPred		0.55		.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;
MVP		0.96
MPC		0.12
ClinPred		0.83	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909384; hg19: chr16-56919240;