16-56887928-G-A

Variant names:

• chr16-56887928-G-A
• rs36049418
• NM_001126108.2:c.2182G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001126108.2(SLC12A3):​c.2182G>A​(p.Ala728Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,609,578 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 30)
  • Exomes 𝑓: 0.019 (353 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.13
• Publications: 19 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001126108.2
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009306401).
• BP6: Variant 16-56887928-G-A is Benign according to our data. Variant chr16-56887928-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1932/151094) while in subpopulation NFE AF = 0.0196 (1330/67804). AF 95% confidence interval is 0.0187. There are 19 homozygotes in GnomAd4. There are 901 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.2182G>A	p.Ala728Thr	missense	Exon 18 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2182G>A	p.Ala728Thr	missense	Exon 18 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2179G>A	p.Ala727Thr	missense	Exon 18 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.2182G>A	p.Ala728Thr	missense	Exon 18 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2182G>A	p.Ala728Thr	missense	Exon 18 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2179G>A	p.Ala727Thr	missense	Exon 18 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1933 AN: 150986 Hom.: 19 Cov.: 30

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0107

Gnomad FIN AF: 0.00752

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0121

GnomAD2 exomes AF: 0.0121 AC: 3042 AN: 251000 AF XY: 0.0129

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00989

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0194 AC: 28262 AN: 1458484 Hom.: 353 Cov.: 30 AF XY: 0.0189 AC XY: 13750 AN XY: 725638

African (AFR) AF: 0.00329 AC: 110 AN: 33400

American (AMR) AF: 0.00575 AC: 257 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 289 AN: 26050

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39622

South Asian (SAS) AF: 0.0103 AC: 890 AN: 86230

European-Finnish (FIN) AF: 0.00936 AC: 495 AN: 52890

Middle Eastern (MID) AF: 0.00750 AC: 43 AN: 5736

European-Non Finnish (NFE) AF: 0.0227 AC: 25205 AN: 1109682

Other (OTH) AF: 0.0161 AC: 970 AN: 60206

GnomAD4 genome AF: 0.0128 AC: 1932 AN: 151094 Hom.: 19 Cov.: 30 AF XY: 0.0122 AC XY: 901 AN XY: 73792

African (AFR) AF: 0.00409 AC: 168 AN: 41112

American (AMR) AF: 0.0115 AC: 174 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.0105 AC: 50 AN: 4778

European-Finnish (FIN) AF: 0.00752 AC: 78 AN: 10372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0196 AC: 1330 AN: 67804

Other (OTH) AF: 0.0120 AC: 25 AN: 2092

Alfa AF: 0.0162 Hom.: 40

Bravo AF: 0.0129

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0121 AC: 1465

EpiCase AF: 0.0196

EpiControl AF: 0.0183

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial hypokalemia-hypomagnesemia (4)
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.7
DANN	Benign	0.86
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.38	N
PhyloP100		-1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.17
Sift	Benign	0.23	T
Sift4G	Benign	0.71	T
Polyphen		0.0010	B
Vest4		0.053
MPC		0.085
ClinPred		0.00031	T
GERP RS		-0.68
Varity_R		0.064
gMVP		0.68
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs36049418; hg19: chr16-56921840; COSMIC: COSV52635583;