16-56894594-G-T

Position:

• chr16-56894594-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001126108.2(SLC12A3):​c.2585G>T​(p.Arg862Leu) 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. 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. R862C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2585G>T	p.Arg862Leu	missense_variant	22/26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2612G>T	p.Arg871Leu	missense_variant	22/26		NP_000330.3
SLC12A3	NM_001126107.2	c.2609G>T	p.Arg870Leu	missense_variant	22/26		NP_001119579.2
SLC12A3	NM_001410896.1	c.2582G>T	p.Arg861Leu	missense_variant	22/26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2585G>T	p.Arg862Leu	missense_variant	22/26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2612G>T	p.Arg871Leu	missense_variant	22/26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2609G>T	p.Arg870Leu	missense_variant	22/26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2582G>T	p.Arg861Leu	missense_variant	22/26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.4	.;.;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.95
MutPred		0.70		.;.;Loss of MoRF binding (P = 0.0451);.;
MVP		0.98
MPC		0.51
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs267607051; hg19: chr16-56928506;