chr1-40303808-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_001852.4(COL9A2):āc.1400A>Gā(p.Gln467Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000262 in 1,564,664 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. Q467E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001852.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL9A2 | NM_001852.4 | c.1400A>G | p.Gln467Arg | missense_variant, splice_region_variant | 27/32 | ENST00000372748.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL9A2 | ENST00000372748.8 | c.1400A>G | p.Gln467Arg | missense_variant, splice_region_variant | 27/32 | 1 | NM_001852.4 | P1 | |
COL9A2 | ENST00000482722.5 | n.1703A>G | splice_region_variant, non_coding_transcript_exon_variant | 26/31 | 1 | ||||
COL9A2 | ENST00000427563.1 | n.211A>G | splice_region_variant, non_coding_transcript_exon_variant | 5/7 | 3 | ||||
COL9A2 | ENST00000466267.1 | n.365A>G | splice_region_variant, non_coding_transcript_exon_variant | 7/11 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000277 AC: 42AN: 151814Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000482 AC: 79AN: 163758Hom.: 1 AF XY: 0.000507 AC XY: 45AN XY: 88706
GnomAD4 exome AF: 0.000260 AC: 368AN: 1412850Hom.: 3 Cov.: 34 AF XY: 0.000292 AC XY: 204AN XY: 698230
GnomAD4 genome AF: 0.000277 AC: 42AN: 151814Hom.: 1 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74162
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2023 | Variant summary: COL9A2 c.1400A>G (p.Gln467Arg) results in a conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00048 in 163758 control chromosomes in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.1400A>G in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=4) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 15, 2018 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2020 | - - |
Epiphyseal dysplasia, multiple, 2;C3280342:Stickler syndrome, type 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Epiphyseal dysplasia, multiple, 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
COL9A2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 05, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at