chr16-56865240-C-G

Variant names:

• chr16-56865240-C-G
• rs1365506259
• NM_001126108.2:c.5C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001126108.2(SLC12A3):​c.5C>G​(p.Ala2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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.

• PM1: In a topological_domain Cytoplasmic (size 134) in uniprot entity S12A3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.5C>G	p.Ala2Gly	missense_variant	Exon 1 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 19, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.34	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.25	N;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.52
MutPred		0.18		Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);
MVP		0.94
MPC		0.45
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.50

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: rs1365506259; hg19: chr16-56899152;