chr21-46124919-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5
The NM_001849.4(COL6A2):c.1769C>A(p.Thr590Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000013 in 1,612,786 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T590M) has been classified as Likely benign.
Frequency
Consequence
NM_001849.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1769C>A | p.Thr590Lys | missense_variant, splice_region_variant | 23/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.1769C>A | p.Thr590Lys | missense_variant, splice_region_variant | 23/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.1769C>A | p.Thr590Lys | missense_variant, splice_region_variant | 23/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1769C>A | p.Thr590Lys | missense_variant, splice_region_variant | 23/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.1769C>A | p.Thr590Lys | missense_variant, splice_region_variant | 23/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.1769C>A | p.Thr590Lys | missense_variant, splice_region_variant | 22/27 | 5 | |||
COL6A2 | ENST00000413758.1 | c.392C>A | p.Thr131Lys | missense_variant, splice_region_variant | 8/11 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000679 AC: 17AN: 250244Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135696
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460576Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 726592
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 14, 2022 | 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1412838). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is present in population databases (rs142709940, gnomAD 0.1%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 590 of the COL6A2 protein (p.Thr590Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at