rs375605948
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_000891.3(KCNJ2):c.208G>A(p.Ala70Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A70S) has been classified as Likely benign.
Frequency
Consequence
NM_000891.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | ENST00000243457.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ2 | ENST00000243457.4 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | 1 | NM_000891.3 | P1 | |
KCNJ2 | ENST00000535240.1 | c.208G>A | p.Ala70Thr | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251482Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135908
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2012 | p.Ala70Thr (GCA>ACA): c.208 G>A in exon 2 of the KCNJ2 gene (NM_000891.2). The Ala70Thr variant in the KCNJ2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ala70Thr results in a non-conservative amino acid substitution of a non-polar Alanine with a neutral, polar Threonine at a residue that is conserved across species. The NHLBI ESP Exome Variant Server reports Ala70Thr was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In addition, mutations in nearby codons (Tyr68Asp, Asp71Asn, Asp71Tyr, Asp71Val) have been reported in association with LQTS, supporting the functional importance of this region of the protein. However, in silico analysis predicts Ala70Thr may have a benign effect on the protein structure/function.In summary, the clinical significance of the Ala70Thr variant in the KCNJ2 gene is currently unknown. The variant is found in LQT panel(s). - |
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 70 of the KCNJ2 protein (p.Ala70Thr). This variant is present in population databases (rs375605948, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KCNJ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 190807). 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 not expected to disrupt KCNJ2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2021 | The p.A70T variant (also known as c.208G>A), located in coding exon 1 of the KCNJ2 gene, results from a G to A substitution at nucleotide position 208. The alanine at codon 70 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at