NM_001126108.2:c.1925+72C>G

Variant names:

• chr16-56885436-C-G
• rs12596776
• NM_001126108.2:c.1925+72C>G

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.1925+72C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0873 in 1,003,100 control chromosomes in the GnomAD database, including 4,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (633 hom., cov: 32)
  • Exomes 𝑓: 0.088 (3575 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0950
• Publications: 21 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=-0.8).
• BP6: Variant 16-56885436-C-G is Benign according to our data. Variant chr16-56885436-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1184681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1925+72C>G		intron_variant	Intron 15 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1925+72C>G		intron_variant	Intron 15 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.1922+72C>G		intron_variant	Intron 15 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.1922+72C>G		intron_variant	Intron 15 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1925+72C>G		intron_variant	Intron 15 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1925+72C>G		intron_variant	Intron 15 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1922+72C>G		intron_variant	Intron 15 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1922+72C>G		intron_variant	Intron 15 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0832 AC: 12649 AN: 152090 Hom.: 631 Cov.: 32

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0486

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0997

Gnomad OTH AF: 0.0995

GnomAD4 exome AF: 0.0880 AC: 74911 AN: 850892 Hom.: 3575 AF XY: 0.0891 AC XY: 39229 AN XY: 440308

African (AFR) AF: 0.0519 AC: 1100 AN: 21186

American (AMR) AF: 0.0582 AC: 2036 AN: 34964

Ashkenazi Jewish (ASJ) AF: 0.0880 AC: 1920 AN: 21828

East Asian (EAS) AF: 0.0312 AC: 1038 AN: 33260

South Asian (SAS) AF: 0.0771 AC: 5266 AN: 68336

European-Finnish (FIN) AF: 0.124 AC: 5616 AN: 45382

Middle Eastern (MID) AF: 0.128 AC: 562 AN: 4386

European-Non Finnish (NFE) AF: 0.0925 AC: 53811 AN: 581522

Other (OTH) AF: 0.0890 AC: 3562 AN: 40028

GnomAD4 genome AF: 0.0832 AC: 12662 AN: 152208 Hom.: 633 Cov.: 32 AF XY: 0.0843 AC XY: 6270 AN XY: 74418

African (AFR) AF: 0.0528 AC: 2195 AN: 41538

American (AMR) AF: 0.0778 AC: 1190 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.0485 AC: 251 AN: 5178

South Asian (SAS) AF: 0.0752 AC: 363 AN: 4824

European-Finnish (FIN) AF: 0.126 AC: 1331 AN: 10586

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0997 AC: 6783 AN: 68004

Other (OTH) AF: 0.0980 AC: 207 AN: 2112

Alfa AF: 0.0326 Hom.: 27

Bravo AF: 0.0780

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hypokalemia-hypomagnesemia Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Likely 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	-0.80
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		-0.095
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs12596776; hg19: chr16-56919348;