rs79351185

Variant names:

• chr16-56884085-C-A
• rs79351185
• NM_001126108.2:c.1706C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56884085-C-A
• chr16-56884085-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 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
• Publications: 20 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• 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, 0.916

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.1706C>A	p.Ala569Glu	missense	Exon 14 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1706C>A	p.Ala569Glu	missense	Exon 14 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1703C>A	p.Ala568Glu	missense	Exon 14 of 26	NP_001119579.2	P55017-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.1706C>A	p.Ala569Glu	missense	Exon 14 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1706C>A	p.Ala569Glu	missense	Exon 14 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1703C>A	p.Ala568Glu	missense	Exon 14 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251174 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hypokalemia-hypomagnesemia (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.026	D
Polyphen		0.052	B
Vest4		0.74
MutPred		0.82		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

Other links and lift over

dbSNP: rs79351185; hg19: chr16-56917997;