NM_001126108.2:c.1732G>C

Variant names:

• chr16-56884111-G-C
• rs139329616
• NM_001126108.2:c.1732G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001126108.2(SLC12A3):​c.1732G>C​(p.Val578Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V578M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.87
• Publications: 22 publications found

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]

SLC12A3 Gene-Disease associations (from GenCC):

• Gitelman syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001126108.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.1732G>C	p.Val578Leu	missense	Exon 14 of 26	NP_001119580.2
	SLC12A3	NM_000339.3		c.1732G>C	p.Val578Leu	missense	Exon 14 of 26	NP_000330.3
	SLC12A3	NM_001126107.2		c.1729G>C	p.Val577Leu	missense	Exon 14 of 26	NP_001119579.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1732G>C	p.Val578Leu	missense	Exon 14 of 26	ENSP00000456149.2
	SLC12A3	ENST00000438926.6	TSL:1	c.1732G>C	p.Val578Leu	missense	Exon 14 of 26	ENSP00000402152.2
	SLC12A3	ENST00000566786.5	TSL:1	c.1729G>C	p.Val577Leu	missense	Exon 14 of 26	ENSP00000457552.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

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.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.2	L
PhyloP100		9.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.81
Sift	Benign	0.12	T
Sift4G	Benign	0.28	T
Polyphen		0.29	B
Vest4		0.92
MutPred		0.66		Gain of glycosylation at S577 (P = 0.1577)
MVP		0.96
MPC		0.13
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.89

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

Other links and lift over

dbSNP: rs139329616; hg19: chr16-56918023;