chr1-40301201-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001852.4(COL9A2):c.2051G>A(p.Gly684Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
COL9A2
NM_001852.4 missense
NM_001852.4 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 4.34
Genes affected
COL9A2 (HGNC:2218): (collagen type IX alpha 2 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.774
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL9A2 | NM_001852.4 | c.2051G>A | p.Gly684Glu | missense_variant | 32/32 | ENST00000372748.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL9A2 | ENST00000372748.8 | c.2051G>A | p.Gly684Glu | missense_variant | 32/32 | 1 | NM_001852.4 | P1 | |
COL9A2 | ENST00000482722.5 | n.2354G>A | non_coding_transcript_exon_variant | 31/31 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250530Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135640
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461468Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727044
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | COL9A2: PM2, PP3, BP1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 2144325). This variant has not been reported in the literature in individuals affected with COL9A2-related conditions. This variant is present in population databases (rs765273618, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 684 of the COL9A2 protein (p.Gly684Glu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at