16-56885363-CGC-TCT

Variant names:

• chr16-56885363-CGG-TCT
• NM_001126108.2:c.1924_1925+1delCGGinsTCT
• SLC12A3 p.Arg642Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP2

The NM_001126108.2(SLC12A3):​c.1924_1925+1delCGGinsTCT​(p.Arg642Ser) variant causes a splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R642C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC12A3 NM_001126108.2 splice_donor, missense, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.94
• 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.5, offset of -41, new splice context is: tcgGTgggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 138 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: -0.93606 (below the threshold of 3.09). Trascript score misZ: 0.71313 (below the threshold of 3.09). GenCC associations: The gene is linked to Gitelman syndrome.

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.1924_1925+1delCGGinsTCT	p.Arg642Ser	splice_donor missense splice_region intron	N/A	NP_001119580.2	P55017-1
	SLC12A3	NM_000339.3		c.1924_1925+1delCGGinsTCT	p.Arg642Ser	splice_donor missense splice_region intron	N/A	NP_000330.3	P55017-2
	SLC12A3	NM_001126107.2		c.1921_1922+1delCGGinsTCT	p.Arg641Ser	splice_donor missense splice_region 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.1924_1925+1delCGGinsTCT	p.Arg642Ser	splice_donor missense splice_region intron	N/A	ENSP00000456149.2	P55017-1
	SLC12A3	ENST00000438926.6	TSL:1	c.1924_1925+1delCGGinsTCT	p.Arg642Ser	splice_donor missense splice_region intron	N/A	ENSP00000402152.2	P55017-2
	SLC12A3	ENST00000566786.5	TSL:1	c.1921_1922+1delCGGinsTCT	p.Arg641Ser	splice_donor missense splice_region intron	N/A	ENSP00000457552.1	P55017-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-56919275;