2-237324816-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BS1_Supporting
The NM_004369.4(COL6A3):c.9494-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004369.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.9494-2A>G | splice_acceptor_variant, intron_variant | Intron 43 of 43 | ENST00000295550.9 | NP_004360.2 | ||
COL6A3 | NM_057167.4 | c.8876-2A>G | splice_acceptor_variant, intron_variant | Intron 42 of 42 | NP_476508.2 | |||
COL6A3 | NM_057166.5 | c.7673-2A>G | splice_acceptor_variant, intron_variant | Intron 40 of 40 | NP_476507.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 151992Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000363 AC: 9AN: 247944Hom.: 0 AF XY: 0.0000373 AC XY: 5AN XY: 134192
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461168Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726838
GnomAD4 genome AF: 0.000230 AC: 35AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:2
Canonical splice site variant with an unclear effect on protein function; Has not been previously published as pathogenic or benign to our knowledge -
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Bethlem myopathy 1A Uncertain:1
This sequence change affects an acceptor splice site in intron 43 of the COL6A3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs142546062, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 576775). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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