16-56878020-GTCCC-GTCCCTCCC

Variant names:

• chr16-56878020-G-GTCCC
• rs3217425
• NM_001126108.2:c.1096-46_1096-43dupCCTC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001126108.2(SLC12A3):​c.1096-46_1096-43dupCCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000745 in 510,404 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.837
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1096-46_1096-43dupCCTC		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1096-46_1096-43dupCCTC		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1093-46_1093-43dupCCTC		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.1096-57_1096-56insTCCC		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1096-57_1096-56insTCCC		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1093-57_1093-56insTCCC		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.0000745 AC: 38 AN: 510404 Hom.: 0 AF XY: 0.0000565 AC XY: 15 AN XY: 265486

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11958

American (AMR) AF: 0.000117 AC: 3 AN: 25654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10430

East Asian (EAS) AF: 0.0000602 AC: 1 AN: 16612

South Asian (SAS) AF: 0.000119 AC: 6 AN: 50486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1628

European-Non Finnish (NFE) AF: 0.0000680 AC: 24 AN: 352806

Other (OTH) AF: 0.000174 AC: 4 AN: 22950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3217425; hg19: chr16-56911932;