16-56892916-T-C

Variant names:

• chr16-56892916-T-C
• rs2278489
• NM_001126108.2:c.2420-37T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.2420-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,568,198 control chromosomes in the GnomAD database, including 233,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26753 hom., cov: 35)
  • Exomes 𝑓: 0.54 (206424 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.987
• Publications: 10 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-56892916-T-C is Benign according to our data. Variant chr16-56892916-T-C is described in ClinVar as Benign. ClinVar VariationId is 1184683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2420-37T>C		intron_variant	Intron 20 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.2447-37T>C		intron_variant	Intron 20 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.2444-37T>C		intron_variant	Intron 20 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.2417-37T>C		intron_variant	Intron 20 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2420-37T>C		intron_variant	Intron 20 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.2447-37T>C		intron_variant	Intron 20 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.2444-37T>C		intron_variant	Intron 20 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.2417-37T>C		intron_variant	Intron 20 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89529 AN: 152170 Hom.: 26721 Cov.: 35

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.601

GnomAD2 exomes AF: 0.567 AC: 136085 AN: 240136 AF XY: 0.558

Gnomad AFR exome AF: 0.687

Gnomad AMR exome AF: 0.612

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.621

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.532

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.538 AC: 761601 AN: 1415910 Hom.: 206424 Cov.: 23 AF XY: 0.537 AC XY: 379232 AN XY: 706660

African (AFR) AF: 0.695 AC: 22622 AN: 32536

American (AMR) AF: 0.610 AC: 26873 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 16326 AN: 25764

East Asian (EAS) AF: 0.630 AC: 24769 AN: 39324

South Asian (SAS) AF: 0.504 AC: 42815 AN: 84888

European-Finnish (FIN) AF: 0.580 AC: 30725 AN: 52972

Middle Eastern (MID) AF: 0.590 AC: 3312 AN: 5612

European-Non Finnish (NFE) AF: 0.524 AC: 561488 AN: 1071998

Other (OTH) AF: 0.556 AC: 32671 AN: 58752

GnomAD4 genome AF: 0.588 AC: 89615 AN: 152288 Hom.: 26753 Cov.: 35 AF XY: 0.591 AC XY: 44015 AN XY: 74440

African (AFR) AF: 0.679 AC: 28244 AN: 41576

American (AMR) AF: 0.596 AC: 9116 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2218 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3267 AN: 5172

South Asian (SAS) AF: 0.498 AC: 2403 AN: 4822

European-Finnish (FIN) AF: 0.591 AC: 6268 AN: 10612

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36020 AN: 68012

Other (OTH) AF: 0.601 AC: 1268 AN: 2110

Alfa AF: 0.529 Hom.: 2226

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypokalemia-hypomagnesemia Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.38
DANN	Benign	0.73
PhyloP100		-0.99
Mutation Taster		=7/93	disease causing

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: rs2278489; hg19: chr16-56926828; COSMIC: COSV52636947;