rs201625904
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_020987.5(ANK3):c.9935C>T(p.Ala3312Val) variant causes a missense change. The variant allele was found at a frequency of 0.000493 in 1,613,984 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020987.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000959 AC: 146AN: 152192Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000493 AC: 123AN: 249546Hom.: 0 AF XY: 0.000497 AC XY: 67AN XY: 134828
GnomAD4 exome AF: 0.000445 AC: 650AN: 1461792Hom.: 2 Cov.: 34 AF XY: 0.000481 AC XY: 350AN XY: 727200
GnomAD4 genome AF: 0.000959 AC: 146AN: 152192Hom.: 2 Cov.: 32 AF XY: 0.00121 AC XY: 90AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
ANK3: BS2 -
The A3312V variant in the ANK3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A3312V variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A3312V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A3312V as a variant of uncertain significance. -
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3312 of the ANK3 protein (p.Ala3312Val). This variant is present in population databases (rs201625904, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 377485). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ANK3 protein function with a negative predictive value of 80%. 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. -
not specified Uncertain:1
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Intellectual disability-hypotonia-spasticity-sleep disorder syndrome Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at