16-56865236-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_001126108.2(SLC12A3):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,224 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.36

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.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001126108.2 (SLC12A3) was described as [Pathogenic] in ClinVar as 945564
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-56865236-A-G is Pathogenic according to our data. Variant chr16-56865236-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1684155.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1A>G	p.Met1?	start_lost	1/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1A>G	p.Met1?	start_lost	1/26
SLC12A3	NM_001126107.2	c.1A>G	p.Met1?	start_lost	1/26
SLC12A3	NM_001410896.1	c.1A>G	p.Met1?	start_lost	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1A>G	p.Met1?	start_lost	1/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1A>G	p.Met1?	start_lost	1/26	1		A1
SLC12A3	ENST00000566786.5	c.1A>G	p.Met1?	start_lost	1/26	1		P4
SLC12A3	ENST00000262502.5	c.1A>G	p.Met1?	start_lost	1/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248774 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

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: 1461224 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726932

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP

Apr 27, 2022

ACMG criteria used: PVS1, PS1, PM1, PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.66	N;N;N;N
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.076	T;T;T;T
Polyphen		0.99	D;D;P;.
Vest4		0.97
MutPred		0.96		Loss of solvent accessibility (P = 0.1301);Loss of solvent accessibility (P = 0.1301);Loss of solvent accessibility (P = 0.1301);Loss of solvent accessibility (P = 0.1301);
MVP		0.95
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.76

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: rs1319085522; hg19: chr16-56899148;