rs199992321
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_004370.6(COL12A1):c.2496A>T(p.Leu832Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,234 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. L832I) has been classified as Uncertain significance.
Frequency
Consequence
NM_004370.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL12A1 | NM_004370.6 | c.2496A>T | p.Leu832Phe | missense_variant | 13/66 | ENST00000322507.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL12A1 | ENST00000322507.13 | c.2496A>T | p.Leu832Phe | missense_variant | 13/66 | 1 | NM_004370.6 | P4 | |
COL12A1 | ENST00000345356.10 | c.74-22770A>T | intron_variant | 1 | |||||
COL12A1 | ENST00000483888.6 | c.2496A>T | p.Leu832Phe | missense_variant | 13/65 | 5 | A1 | ||
COL12A1 | ENST00000416123.6 | c.2496A>T | p.Leu832Phe | missense_variant | 12/63 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000521 AC: 13AN: 249388Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135294
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727244
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 832 of the COL12A1 protein (p.Leu832Phe). This variant is present in population databases (rs199992321, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542487). 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 COL12A1 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at