rs61746763

chr16-56885304-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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:6
• Conservation: PhyloP100: 9.21

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001126108.2
• 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 [Likely_benign]. Clinvar id is 255882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56885304-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1865A>G	p.Asn622Ser	missense_variant	15/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1865A>G	p.Asn622Ser	missense_variant	15/26
SLC12A3	NM_001126107.2	c.1862A>G	p.Asn621Ser	missense_variant	15/26
SLC12A3	NM_001410896.1	c.1862A>G	p.Asn621Ser	missense_variant	15/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1865A>G	p.Asn622Ser	missense_variant	15/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1865A>G	p.Asn622Ser	missense_variant	15/26	1		A1
SLC12A3	ENST00000566786.5	c.1862A>G	p.Asn621Ser	missense_variant	15/26	1		P4
SLC12A3	ENST00000262502.5	c.1862A>G	p.Asn621Ser	missense_variant	15/26	5		A1

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

GnomAD3 exomes AF: 0.00477 AC: 777 AN: 162868 Hom.: 12 AF XY: 0.00363 AC XY: 312 AN XY: 85962

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 SAS exome AF: 0.000217

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

Gnomad4 AFR exome AF: 0.0473

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.0309

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.00547

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

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.0312

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00422 Hom.: 15

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypokalemia-hypomagnesemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T;T;T
MetaRNN	Benign	0.0055	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N;N;N;N
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.66	T;T;T;T
Polyphen		0.048	B;B;P;.
Vest4		0.83
MVP		0.95
MPC		0.21
ClinPred		0.027	T
GERP RS		5.4
Varity_R		0.19
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs61746763; hg19: chr16-56919216;