rs79351185

chr16-56884085-C-Achr16-56884085-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001126108.2(SLC12A3):c.1706C>A(p.Ala569Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A569V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1706C>A	p.Ala569Glu	missense_variant	14/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1706C>A	p.Ala569Glu	missense_variant	14/26
SLC12A3	NM_001126107.2	c.1703C>A	p.Ala568Glu	missense_variant	14/26
SLC12A3	NM_001410896.1	c.1703C>A	p.Ala568Glu	missense_variant	14/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1706C>A	p.Ala569Glu	missense_variant	14/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1706C>A	p.Ala569Glu	missense_variant	14/26	1		A1
SLC12A3	ENST00000566786.5	c.1703C>A	p.Ala568Glu	missense_variant	14/26	1		P4
SLC12A3	ENST00000262502.5	c.1703C>A	p.Ala568Glu	missense_variant	14/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251174 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;N;N;N
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.052	B;B;B;.
Vest4		0.74
MutPred		0.82		.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.95
MPC		0.12
ClinPred		0.53	D
GERP RS		3.6
Varity_R		0.32
gMVP		0.96

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: rs79351185; hg19: chr16-56917997;