rs121912889
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001844.5(COL2A1):c.4172A>G(p.Tyr1391Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1391H) has been classified as Pathogenic.
Frequency
Consequence
NM_001844.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL2A1 | NM_001844.5 | c.4172A>G | p.Tyr1391Cys | missense_variant | 53/54 | ENST00000380518.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.4172A>G | p.Tyr1391Cys | missense_variant | 53/54 | 1 | NM_001844.5 | P1 | |
COL2A1 | ENST00000337299.7 | c.3965A>G | p.Tyr1322Cys | missense_variant | 52/53 | 1 | |||
COL2A1 | ENST00000493991.5 | n.3258A>G | non_coding_transcript_exon_variant | 36/37 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Platyspondylic dysplasia, Torrance type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 20, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: "Not Available"; Align-GVGD: "Class C65"). This variant has been observed in individual(s) with clinical features of COL2A1-related conditions (PMID: 14729840, 17726487, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17389). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 1391 of the COL2A1 protein (p.Tyr1391Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. - |
Spondyloperipheral dysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at