rs150358489

chr16-56879102-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001126108.2(SLC12A3):c.1210G>A(p.Val404Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,118 control chromosomes in the GnomAD database, including 3 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V404V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: SLC12A3 NM_001126108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.435

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043110847).
• BP6: Variant 16-56879102-G-A is Benign according to our data. Variant chr16-56879102-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A3	NM_001126108.2	c.1210G>A	p.Val404Ile	missense_variant	10/26	ENST00000563236.6
SLC12A3	NM_000339.3	c.1210G>A	p.Val404Ile	missense_variant	10/26
SLC12A3	NM_001126107.2	c.1207G>A	p.Val403Ile	missense_variant	10/26
SLC12A3	NM_001410896.1	c.1207G>A	p.Val403Ile	missense_variant	10/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1210G>A	p.Val404Ile	missense_variant	10/26	1	NM_001126108.2	A1
SLC12A3	ENST00000438926.6	c.1210G>A	p.Val404Ile	missense_variant	10/26	1		A1
SLC12A3	ENST00000566786.5	c.1207G>A	p.Val403Ile	missense_variant	10/26	1		P4
SLC12A3	ENST00000262502.5	c.1207G>A	p.Val403Ile	missense_variant	10/26	5		A1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.000955

GnomAD3 exomes AF: 0.000497 AC: 124 AN: 249412 Hom.: 0 AF XY: 0.000333 AC XY: 45 AN XY: 135022

Gnomad AFR exome AF: 0.00687

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1460808 Hom.: 1 Cov.: 33 AF XY: 0.000154 AC XY: 112 AN XY: 726660

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.000471

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74478

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.00204

ESP6500AA AF: 0.00751 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000511 AC: 62

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Familial hypokalemia-hypomagnesemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	9.3
Dann	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0043	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.010	N;N;N;N
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.035
MVP		0.71
MPC		0.071
ClinPred		0.0038	T
GERP RS		1.1
Varity_R		0.036
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs150358489; hg19: chr16-56913014;