NM_001126108.2:c.55C>A

Variant names:

• chr16-56865290-C-A
• rs374055486
• NM_001126108.2:c.55C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001126108.2(SLC12A3):​c.55C>A​(p.Arg19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.36640346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.55C>A	p.Arg19Ser	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.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.55C>A	p.Arg19Ser	missense_variant	Exon 1 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.056	T;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.40
MutPred		0.40		Loss of methylation at R19 (P = 0.0145);Loss of methylation at R19 (P = 0.0145);Loss of methylation at R19 (P = 0.0145);Loss of methylation at R19 (P = 0.0145);
MVP		0.94
MPC		0.50
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.74

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: rs374055486; hg19: chr16-56899202;