NM_004370.6:c.7477G>A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6
The NM_004370.6(COL12A1):c.7477G>A(p.Glu2493Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004370.6 missense
Scores
Clinical Significance
Conservation
Publications
- Bethlem myopathy 2Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- Bethlem myopathy 2Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
- Ullrich congenital muscular dystrophy 2Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Bethlem myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Ullrich congenital muscular dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 248962 AF XY: 0.0000222 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461300Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 726944 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74352 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1
The E2493K variant in the COL12A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E2493K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E2493K 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 in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E2493K as a variant of uncertain significance. -
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at