rs760093841
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP2PP3_ModeratePP5
The NM_001844.5(COL2A1):c.3655G>T(p.Asp1219Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1219G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001844.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL2A1 | NM_001844.5 | c.3655G>T | p.Asp1219Tyr | missense_variant | 51/54 | ENST00000380518.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.3655G>T | p.Asp1219Tyr | missense_variant | 51/54 | 1 | NM_001844.5 | P1 | |
COL2A1 | ENST00000337299.7 | c.3448G>T | p.Asp1150Tyr | missense_variant | 50/53 | 1 | |||
COL2A1 | ENST00000546974.1 | n.508G>T | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
COL2A1 | ENST00000493991.5 | n.2741G>T | non_coding_transcript_exon_variant | 34/37 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2017 | The D1219Y variant in the COL2A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D1219Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D1219Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. A missense variant in the same residue (D1219H) has been reported in association with spondyloepimetaphyseal dysplasia, supporting the functional importance of this residue (Hammarsjo et al., 2016). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the D1219Y variant is a strong candidate for a pathogenic variant; however the possibility it may be a rare benign variant cannot be completely excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at