16-56902509-G-T

Variant names:

• chr16-56902509-G-T
• rs199974259
• NM_001126108.2:c.2856+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_001126108.2(SLC12A3):​c.2856+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,600,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001200434: Studies have shown that disruption of this splice site results in skipping of exon 24, and produces a non-functional protein and/or introduces a premature termination codon (PMID:9596079).; SCV002766745: RT-PCR studies using cDNA from an individual with Gitelman syndrome showed the presence of a wild type (WT) length fragment and an additional shorter fragment compared to a healthy individual; however, the deletion of exon 24 was not confirmed using Sanger sequencing (PMID:9596079).".

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: SLC12A3 NM_001126108.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 9.35
• 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001200434: Studies have shown that disruption of this splice site results in skipping of exon 24, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9596079).; SCV002766745: RT-PCR studies using cDNA from an individual with Gitelman syndrome showed the presence of a wild type (WT) length fragment and an additional shorter fragment compared to a healthy individual; however, the deletion of exon 24 was not confirmed using Sanger sequencing (PMID: 9596079).
• PP5: Variant 16-56902509-G-T is Pathogenic according to our data. Variant chr16-56902509-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2856+1G>T		splice_donor intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.2883+1G>T		splice_donor intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.2880+1G>T		splice_donor 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.2856+1G>T		splice_donor intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.2883+1G>T		splice_donor intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.2880+1G>T		splice_donor intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes AF: 0.000219 AC: 33 AN: 151014 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000369

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000223 AC: 56 AN: 250878 AF XY: 0.000236

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000503 AC: 729 AN: 1449680 Hom.: 0 Cov.: 42 AF XY: 0.000506 AC XY: 365 AN XY: 721376

African (AFR) AF: 0.000120 AC: 4 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.000644 AC: 710 AN: 1102640

Other (OTH) AF: 0.000217 AC: 13 AN: 59820

GnomAD4 genome AF: 0.000219 AC: 33 AN: 151014 Hom.: 0 Cov.: 29 AF XY: 0.000217 AC XY: 16 AN XY: 73660

African (AFR) AF: 0.000195 AC: 8 AN: 40992

American (AMR) AF: 0.00 AC: 0 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000369 AC: 25 AN: 67736

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.000448 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000173 AC: 21

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Familial hypokalemia-hypomagnesemia (11)
7	-	-	not provided (7)
1	-	-	Bartter syndrome;C0268450:Familial hypokalemia-hypomagnesemia (1)
1	-	-	Renal tubulopathies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.4
GERP RS		5.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs199974259; hg19: chr16-56936421;