16-56878020-GTCCC-GTCCCTCCCTCCCTCCCTCCCTCCC

Variant names:

• chr16-56878020-G-GTCCCTCCCTCCCTCCCTCCC
• rs3217425
• NM_001126108.2:c.1096-43_1096-42insCCTCCCTCCCTCCCTCCCTC

Variant summary

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

The NM_001126108.2(SLC12A3):​c.1096-43_1096-42insCCTCCCTCCCTCCCTCCCTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 510,520 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000020 (0 hom.)
  • Failed GnomAD Quality Control
• 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 0 ACMG points.

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.1096-43_1096-42insCCTCCCTCCCTCCCTCCCTC		intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1096-43_1096-42insCCTCCCTCCCTCCCTCCCTC		intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1093-43_1093-42insCCTCCCTCCCTCCCTCCCTC		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_1096-56insTCCCTCCCTCCCTCCCTCCC		intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1096-57_1096-56insTCCCTCCCTCCCTCCCTCCC		intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1093-57_1093-56insTCCCTCCCTCCCTCCCTCCC		intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.0000438 AC: 4 AN: 91372 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000213

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000196 AC: 1 AN: 510520 Hom.: 0 AF XY: 0.00000377 AC XY: 1 AN XY: 265550

⚠️ 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: 0.00 AC: 0 AN: 25660

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 16620

South Asian (SAS) AF: 0.0000198 AC: 1 AN: 50498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1630

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 352888

Other (OTH) AF: 0.00 AC: 0 AN: 22954

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000438 AC: 4 AN: 91372 Hom.: 0 Cov.: 26 AF XY: 0.0000697 AC XY: 3 AN XY: 43022

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

African (AFR) AF: 0.0000485 AC: 1 AN: 20602

American (AMR) AF: 0.000235 AC: 2 AN: 8516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2322

East Asian (EAS) AF: 0.00 AC: 0 AN: 2912

South Asian (SAS) AF: 0.00 AC: 0 AN: 2904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 158

European-Non Finnish (NFE) AF: 0.0000213 AC: 1 AN: 46938

Other (OTH) AF: 0.00 AC: 0 AN: 1200

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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;