rs61746763

Variant names:

• chr16-56885304-A-G
• rs61746763
• NM_001126108.2:c.1865A>G

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.1865A>G​(p.Asn622Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,555,576 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (46 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.21
• Publications: 8 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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=0.005542457).
• BP6: Variant 16-56885304-A-G is Benign according to our data. Variant chr16-56885304-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2038/152096) while in subpopulation AFR AF = 0.0444 (1843/41532). AF 95% confidence interval is 0.0427. There are 34 homozygotes in GnomAd4. There are 971 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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.1865A>G	p.Asn622Ser	missense	Exon 15 of 26	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1865A>G	p.Asn622Ser	missense	Exon 15 of 26	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1862A>G	p.Asn621Ser	missense	Exon 15 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.1865A>G	p.Asn622Ser	missense	Exon 15 of 26	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1865A>G	p.Asn622Ser	missense	Exon 15 of 26	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1862A>G	p.Asn621Ser	missense	Exon 15 of 26	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2031 AN: 151978 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.0312

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00477 AC: 777 AN: 162868 AF XY: 0.00363

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.00221

GnomAD4 exome AF: 0.00211 AC: 2967 AN: 1403480 Hom.: 46 Cov.: 30 AF XY: 0.00198 AC XY: 1374 AN XY: 692678

African (AFR) AF: 0.0473 AC: 1506 AN: 31840

American (AMR) AF: 0.00207 AC: 75 AN: 36266

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 778 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36200

South Asian (SAS) AF: 0.000202 AC: 16 AN: 79396

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49468

Middle Eastern (MID) AF: 0.00719 AC: 41 AN: 5706

European-Non Finnish (NFE) AF: 0.000215 AC: 232 AN: 1081234

Other (OTH) AF: 0.00547 AC: 318 AN: 58176

GnomAD4 genome AF: 0.0134 AC: 2038 AN: 152096 Hom.: 34 Cov.: 32 AF XY: 0.0131 AC XY: 971 AN XY: 74328

African (AFR) AF: 0.0444 AC: 1843 AN: 41532

American (AMR) AF: 0.00334 AC: 51 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0312 AC: 108 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4788

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67982

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00609 Hom.: 32

Bravo AF: 0.0153

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0359 AC: 155

ESP6500EA AF: 0.00178 AC: 15

ExAC AF: 0.00284 AC: 314

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial hypokalemia-hypomagnesemia (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.098
Sift	Benign	0.66	T
Sift4G	Benign	0.66	T
Polyphen		0.048	B
Vest4		0.83
MVP		0.95
MPC		0.21
ClinPred		0.027	T
GERP RS		5.4
Varity_R		0.19
gMVP		0.80
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61746763; hg19: chr16-56919216;