chr21-45994228-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_001848.3(COL6A1):c.1397C>T(p.Pro466Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,608,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P466P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001848.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.1397C>T | p.Pro466Leu | missense_variant, splice_region_variant | 20/35 | ENST00000361866.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A1 | ENST00000361866.8 | c.1397C>T | p.Pro466Leu | missense_variant, splice_region_variant | 20/35 | 1 | NM_001848.3 | P1 | |
COL6A1 | ENST00000683550.1 | n.172C>T | splice_region_variant, non_coding_transcript_exon_variant | 1/5 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151820Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000210 AC: 5AN: 237828Hom.: 0 AF XY: 0.0000155 AC XY: 2AN XY: 128938
GnomAD4 exome AF: 0.00000892 AC: 13AN: 1456786Hom.: 0 Cov.: 32 AF XY: 0.00000691 AC XY: 5AN XY: 724096
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151820Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74120
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2021 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with COL6A1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 466 of the COL6A1 protein (p.Pro466Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at