chr16-56885323-G-T

Variant names:

• chr16-56885323-G-T
• rs5802
• NM_001126108.2:c.1884G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001126108.2(SLC12A3):​c.1884G>T​(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S628S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.14
• Publications: 13 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-6.14 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.1884G>T	p.Ser628Ser	synonymous_variant	Exon 15 of 26	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.1884G>T	p.Ser628Ser	synonymous_variant	Exon 15 of 26		NP_000330.3
SLC12A3	NM_001126107.2	c.1881G>T	p.Ser627Ser	synonymous_variant	Exon 15 of 26		NP_001119579.2
SLC12A3	NM_001410896.1	c.1881G>T	p.Ser627Ser	synonymous_variant	Exon 15 of 26		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.1884G>T	p.Ser628Ser	synonymous_variant	Exon 15 of 26	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.1884G>T	p.Ser628Ser	synonymous_variant	Exon 15 of 26	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.1881G>T	p.Ser627Ser	synonymous_variant	Exon 15 of 26	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.1881G>T	p.Ser627Ser	synonymous_variant	Exon 15 of 26	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000613 AC: 1 AN: 163130 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403600 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692728

African (AFR) AF: 0.00 AC: 0 AN: 31850

American (AMR) AF: 0.0000276 AC: 1 AN: 36256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25196

East Asian (EAS) AF: 0.00 AC: 0 AN: 36208

South Asian (SAS) AF: 0.00 AC: 0 AN: 79412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081276

Other (OTH) AF: 0.00 AC: 0 AN: 58180

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.047
DANN	Benign	0.35
PhyloP100		-6.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5802; hg19: chr16-56919235;