12-47979534-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP2PP3

The NM_001844.5(COL2A1):​c.2710C>G​(p.Arg904Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R904C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

COL2A1
NM_001844.5 missense

Scores

8
5
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.892
Variant links:
Genes affected
COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-47979534-G-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the COL2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 376 curated pathogenic missense variants (we use a threshold of 10). The gene has 125 curated benign missense variants. Gene score misZ: 3.2926 (above the threshold of 3.09). Trascript score misZ: 5.3726 (above the threshold of 3.09). GenCC associations: The gene is linked to spondylometaphyseal dysplasia, Schmidt type, spondyloepiphyseal dysplasia congenita, hypochondrogenesis, autosomal dominant rhegmatogenous retinal detachment, spondyloperipheral dysplasia, Kniest dysplasia, familial avascular necrosis of femoral head, spondylometaphyseal dysplasia, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, otospondylomegaepiphyseal dysplasia, autosomal recessive, multiple epiphyseal dysplasia, Beighton type, otospondylomegaepiphyseal dysplasia, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia, Stanescu type, platyspondylic dysplasia, Torrance type, Stickler syndrome type 1, dysspondyloenchondromatosis, vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, avascular necrosis of femoral head, primary, 1, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloepimetaphyseal dysplasia, Strudwick type.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL2A1NM_001844.5 linkc.2710C>G p.Arg904Gly missense_variant Exon 41 of 54 ENST00000380518.8 NP_001835.3 P02458-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL2A1ENST00000380518.8 linkc.2710C>G p.Arg904Gly missense_variant Exon 41 of 54 1 NM_001844.5 ENSP00000369889.3 P02458-2
COL2A1ENST00000337299.7 linkc.2503C>G p.Arg835Gly missense_variant Exon 40 of 53 1 ENSP00000338213.6 P02458-1
COL2A1ENST00000493991.5 linkn.1796C>G non_coding_transcript_exon_variant Exon 24 of 37 2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
D;.
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Benign
1.1
L;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.029
D;D
Sift4G
Benign
0.23
T;T
Polyphen
0.63
P;P
Vest4
0.69
MutPred
0.62
Loss of methylation at R904 (P = 0.0024);.;
MVP
0.96
MPC
0.97
ClinPred
0.99
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.61
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48373317; API