16-56879168-A-T

Position:

• chr16-56879168-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001126108.2(SLC12A3):​c.1276A>T​(p.Asn426Tyr) 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)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.89

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 7 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity S12A3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 16-56879168-A-T is Pathogenic according to our data. Variant chr16-56879168-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 403666.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1276A>T	p.Asn426Tyr	missense_variant	10/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1276A>T	p.Asn426Tyr	missense_variant	10/26
SLC12A3	NM_001126107.2	c.1273A>T	p.Asn425Tyr	missense_variant	10/26
SLC12A3	NM_001410896.1	c.1273A>T	p.Asn425Tyr	missense_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1276A>T	p.Asn426Tyr	missense_variant	10/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1276A>T	p.Asn426Tyr	missense_variant	10/26	1		A1
SLC12A3	ENST00000566786.5	c.1273A>T	p.Asn425Tyr	missense_variant	10/26	1		P4
SLC12A3	ENST00000262502.5	c.1273A>T	p.Asn425Tyr	missense_variant	10/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

clinical testing

Human Genetics Unit, University Of Colombo

-

Two siblings from a Sri Lankan non-consanguineous family presenting with hypokalaemia associated with renal potassium wasting, hypomagnesemia, hypocalciuria and hypereninemic hyperaldosteronism with normal blood pressure underwent genetic testing. It showed that both were homozygotes for a novel missense mutation in exon 10 of the SLC12A3 gene [NM_000339.2, c.1276A>T; p.N426Y], which has not previously been reported in the literature in association with GS. Both siblings had young onset Diabetes with strong family history. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.96	D;D;D;.
Vest4		0.79
MutPred		0.67		.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;
MVP		0.95
MPC		0.50
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.83

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: rs200817545; hg19: chr16-56913080;