rs201575500
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1
The NM_001005361.3(DNM2):āc.1384A>Gā(p.Thr462Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T462I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001005361.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNM2 | NM_001005361.3 | c.1384A>G | p.Thr462Ala | missense_variant | 11/21 | ENST00000389253.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM2 | ENST00000389253.9 | c.1384A>G | p.Thr462Ala | missense_variant | 11/21 | 5 | NM_001005361.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 151854Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000231 AC: 58AN: 251428Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135912
GnomAD4 exome AF: 0.000140 AC: 205AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120AN XY: 727240
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 151974Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74278
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2017 | The T462A variant has been previously reported as a variant of unknown significance in an individual with congenital myopathy who harbored additional variants in other neuromuscular-related genes (Savarese et al., 2014). The T462A variant is observed in 19/66618 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variant in a nearby residue (R465W) has been reported in the Human Gene Mutation Database in association with centronuclear myopathy (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 06, 2023 | - - |
Charcot-Marie-Tooth disease dominant intermediate B Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 23, 2020 | - - |
Autosomal dominant centronuclear myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 20, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at