rs34018054

Variant names:

• chr16-56904273-G-A
• rs34018054
• NM_001126108.2:c.2857-122G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56904273-G-A
• chr16-56904273-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001126108.2(SLC12A3):​c.2857-122G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 936,414 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (3 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.252
• Publications: 1 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]

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-56904273-G-A is Benign according to our data. Variant chr16-56904273-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1186547.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00669 (1019/152330) while in subpopulation AFR AF = 0.023 (955/41566). AF 95% confidence interval is 0.0218. There are 14 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	NM_001126108.2	MANE Select	c.2857-122G>A		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2884-122G>A		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2881-122G>A		intron	N/A	NP_001119579.2	P55017-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A3	ENST00000563236.6	TSL:1 MANE Select	c.2857-122G>A		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2884-122G>A		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2881-122G>A		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.00670 AC: 1020 AN: 152212 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00196 AC: 482 AN: 245738 AF XY: 0.00167

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000925 AC: 725 AN: 784084 Hom.: 3 Cov.: 11 AF XY: 0.000802 AC XY: 334 AN XY: 416238

African (AFR) AF: 0.0276 AC: 551 AN: 19936

American (AMR) AF: 0.00124 AC: 53 AN: 42864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20802

East Asian (EAS) AF: 0.00 AC: 0 AN: 34262

South Asian (SAS) AF: 0.0000276 AC: 2 AN: 72440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49816

Middle Eastern (MID) AF: 0.00115 AC: 5 AN: 4362

European-Non Finnish (NFE) AF: 0.000103 AC: 52 AN: 502566

Other (OTH) AF: 0.00167 AC: 62 AN: 37036

GnomAD4 genome AF: 0.00669 AC: 1019 AN: 152330 Hom.: 14 Cov.: 32 AF XY: 0.00648 AC XY: 483 AN XY: 74486

African (AFR) AF: 0.0230 AC: 955 AN: 41566

American (AMR) AF: 0.00288 AC: 44 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00768

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

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: rs34018054; hg19: chr16-56938185;