16-56885436-C-G

Position:

• chr16-56885436-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1925+72C>G		intron_variant		ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1925+72C>G		intron_variant			NP_000330.3
SLC12A3	NM_001126107.2	c.1922+72C>G		intron_variant			NP_001119579.2
SLC12A3	NM_001410896.1	c.1922+72C>G		intron_variant			NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1925+72C>G		intron_variant		1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1925+72C>G		intron_variant		1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1922+72C>G		intron_variant		1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1922+72C>G		intron_variant		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

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.0582

Gnomad4 ASJ exome AF: 0.0880

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.0771

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0925

Gnomad4 OTH exome AF: 0.0890

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

Gnomad4 AFR AF: 0.0528

Gnomad4 AMR AF: 0.0778

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0485

Gnomad4 SAS AF: 0.0752

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.0997

Gnomad4 OTH AF: 0.0980

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hypokalemia-hypomagnesemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs12596776; hg19: chr16-56919348;