16-56879153-T-G

Variant names:

• chr16-56879153-T-G
• NM_001126108.2:c.1261T>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.1261T>G​(p.Cys421Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.88

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 16-56879153-T-G is Pathogenic according to our data. Variant chr16-56879153-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1256468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1261T>G	p.Cys421Gly	missense_variant	Exon 10 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1261T>G	p.Cys421Gly	missense_variant	Exon 10 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.1258T>G	p.Cys420Gly	missense_variant	Exon 10 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1258T>G	p.Cys420Gly	missense_variant	Exon 10 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1261T>G	p.Cys421Gly	missense_variant	Exon 10 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1261T>G	p.Cys421Gly	missense_variant	Exon 10 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1258T>G	p.Cys420Gly	missense_variant	Exon 10 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1258T>G	p.Cys420Gly	missense_variant	Exon 10 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:1

Mar 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 18, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;.;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Pathogenic	3.5	.;H;H;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.97
MutPred		0.67		.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		0.94
MPC		0.51
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56913065;