rs200278401
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000089.4(COL1A2):āc.52T>Cā(p.Cys18Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.000053 ( 0 hom. )
Consequence
COL1A2
NM_000089.4 missense
NM_000089.4 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 7.08
Genes affected
COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A2. . Gene score misZ 2.1491 (greater than the threshold 3.09). Trascript score misZ 3.5344 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, cardiac valvular type, ehlers-danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, high bone mass osteogenesis imperfecta, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, osteogenesis imperfecta type 4, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.17271164).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.52T>C | p.Cys18Arg | missense_variant | 1/52 | ENST00000297268.11 | NP_000080.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.52T>C | p.Cys18Arg | missense_variant | 1/52 | 1 | NM_000089.4 | ENSP00000297268.6 | ||
ENSG00000285090 | ENST00000644739.1 | n.69+457A>G | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251322Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135842
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GnomAD4 exome AF: 0.0000527 AC: 77AN: 1461816Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30AN XY: 727200
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GnomAD4 genome AF: 0.0000592 AC: 9AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 526891; Landrum et al., 2016) - |
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 526891). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. This variant is present in population databases (rs200278401, gnomAD 0.009%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 18 of the COL1A2 protein (p.Cys18Arg). - |
Postmenopausal osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4303789:Ehlers-Danlos syndrome, cardiac valvular type;CN293783:Ehlers-danlos syndrome, arthrochalasia type, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2024 | The p.C18R variant (also known as c.52T>C), located in coding exon 1 of the COL1A2 gene, results from a T to C substitution at nucleotide position 52. The cysteine at codon 18 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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