chr16-56904332-G-A

Position:

• chr16-56904332-G-A

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.2857-63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,410,554 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (149 hom., cov: 32)
  • Exomes 𝑓: 0.020 (470 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02

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]

MIR6863 (HGNC:49942): (microRNA 6863) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-56904332-G-A is Benign according to our data. Variant chr16-56904332-G-A is described in ClinVar as [Benign]. Clinvar id is 1229810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.2857-63G>A		intron_variant		ENST00000563236.6	NP_001119580.2
MIR6863	NR_106923.1	n.69G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.2857-63G>A		intron_variant		1	NM_001126108.2	ENSP00000456149	A1
MIR6863	ENST00000636112.1	n.69G>A		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5467 AN: 152180 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0733

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0319

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0316 AC: 7947 AN: 251364 Hom.: 216 AF XY: 0.0308 AC XY: 4181 AN XY: 135860

Gnomad AFR exome AF: 0.0765

Gnomad AMR exome AF: 0.0447

Gnomad ASJ exome AF: 0.0670

Gnomad EAS exome AF: 0.0275

Gnomad SAS exome AF: 0.0506

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0333

GnomAD4 exome AF: 0.0196 AC: 24659 AN: 1258256 Hom.: 470 Cov.: 17 AF XY: 0.0204 AC XY: 12960 AN XY: 636388

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.0452

Gnomad4 ASJ exome AF: 0.0681

Gnomad4 EAS exome AF: 0.0235

Gnomad4 SAS exome AF: 0.0483

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0360 AC: 5484 AN: 152298 Hom.: 149 Cov.: 32 AF XY: 0.0361 AC XY: 2690 AN XY: 74472

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.0590

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.0319

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0332 Hom.: 26

Bravo AF: 0.0387

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.1
DANN	Benign	0.77

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: rs12708966; hg19: chr16-56938244; COSMIC: COSV52632572; COSMIC: COSV52632572;