2-237347829-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_004369.4(COL6A3):c.7007C>A(p.Pro2336His) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,611,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P2336L) has been classified as Likely benign.
Frequency
Consequence
NM_004369.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.7007C>A | p.Pro2336His | missense_variant | 31/44 | ENST00000295550.9 | |
COL6A3 | NM_057167.4 | c.6389C>A | p.Pro2130His | missense_variant | 30/43 | ||
COL6A3 | NM_057166.5 | c.5186C>A | p.Pro1729His | missense_variant | 28/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A3 | ENST00000295550.9 | c.7007C>A | p.Pro2336His | missense_variant | 31/44 | 1 | NM_004369.4 | P1 | |
COL6A3 | ENST00000472056.5 | c.5186C>A | p.Pro1729His | missense_variant | 28/41 | 1 | |||
COL6A3 | ENST00000353578.9 | c.6389C>A | p.Pro2130His | missense_variant | 30/43 | 5 | |||
COL6A3 | ENST00000491769.1 | n.1261C>A | non_coding_transcript_exon_variant | 8/20 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000203 AC: 5AN: 246620Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133066
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1459136Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 725426
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74462
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 18, 2023 | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2336 of the COL6A3 protein (p.Pro2336His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL6A3 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at