rs72658198
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_000089.4(COL1A2):c.2565+1G>A variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000089.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.2565+1G>A | splice_donor_variant, intron_variant | Intron 40 of 51 | ENST00000297268.11 | NP_000080.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.2565+1G>A | splice_donor_variant, intron_variant | Intron 40 of 51 | 1 | NM_000089.4 | ENSP00000297268.6 | |||
COL1A2 | ENST00000481570.5 | n.649G>A | non_coding_transcript_exon_variant | Exon 1 of 8 | 2 | |||||
COL1A2 | ENST00000497316.5 | n.*1G>A | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1
This sequence change affects a donor splice site in intron 40 of the COL1A2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with osteogenesis imperfecta, type III (PMID: 26177859). It has also been reported in an individual affected with osteogenesis imperfecta, type IV (PMID: 16705691). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A2 are known to be pathogenic (PMID: 9099837, 3372533). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at