chr12-47982567-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2
The NM_001844.5(COL2A1):c.2236C>T(p.Pro746Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,502 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: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
COL2A1
NM_001844.5 missense
NM_001844.5 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 10.0
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001844.5
PP2
Missense variant where missense usually causes diseases, COL2A1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831
BS2
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL2A1 | NM_001844.5 | c.2236C>T | p.Pro746Ser | missense_variant | 34/54 | ENST00000380518.8 | |
LOC105369752 | XR_944910.2 | n.278+93G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL2A1 | ENST00000380518.8 | c.2236C>T | p.Pro746Ser | missense_variant | 34/54 | 1 | NM_001844.5 | P1 | |
COL2A1 | ENST00000337299.7 | c.2029C>T | p.Pro677Ser | missense_variant | 33/53 | 1 | |||
COL2A1 | ENST00000483376.1 | n.414C>T | non_coding_transcript_exon_variant | 5/8 | 5 | ||||
COL2A1 | ENST00000493991.5 | n.1160C>T | non_coding_transcript_exon_variant | 17/37 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248268Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134600
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461502Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6AN XY: 727076
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Connective tissue disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at P745 (P = 0.0131);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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