rs779160677
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM2PM5PP3_StrongPP5_Very_Strong
The NM_001126108.2(SLC12A3):āc.1844C>Gā(p.Ser615Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,400,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S615L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001126108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A3 | NM_001126108.2 | c.1844C>G | p.Ser615Trp | missense_variant | 15/26 | ENST00000563236.6 | |
SLC12A3 | NM_000339.3 | c.1844C>G | p.Ser615Trp | missense_variant | 15/26 | ||
SLC12A3 | NM_001126107.2 | c.1841C>G | p.Ser614Trp | missense_variant | 15/26 | ||
SLC12A3 | NM_001410896.1 | c.1841C>G | p.Ser614Trp | missense_variant | 15/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A3 | ENST00000563236.6 | c.1844C>G | p.Ser615Trp | missense_variant | 15/26 | 1 | NM_001126108.2 | A1 | |
SLC12A3 | ENST00000438926.6 | c.1844C>G | p.Ser615Trp | missense_variant | 15/26 | 1 | A1 | ||
SLC12A3 | ENST00000566786.5 | c.1841C>G | p.Ser614Trp | missense_variant | 15/26 | 1 | P4 | ||
SLC12A3 | ENST00000262502.5 | c.1841C>G | p.Ser614Trp | missense_variant | 15/26 | 5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000214 AC: 3AN: 1400880Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 691200
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial hypokalemia-hypomagnesemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Jul 29, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2022 | This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 615 of the SLC12A3 protein (p.Ser615Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC12A3-related conditions (PMID: 12112667). ClinVar contains an entry for this variant (Variation ID: 1330263). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function. This variant disrupts the p.Ser615 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 20552229, 22728489, 27303630, 30596175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at