rs201168934
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3
The NM_000089.4(COL1A2):c.2843G>A(p.Arg948His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,674 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R948C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000089.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.2843G>A | p.Arg948His | missense_variant | 44/52 | ENST00000297268.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.2843G>A | p.Arg948His | missense_variant | 44/52 | 1 | NM_000089.4 | P1 | |
COL1A2 | ENST00000469732.1 | n.626G>A | non_coding_transcript_exon_variant | 4/4 | 2 | ||||
COL1A2 | ENST00000478215.1 | n.402G>A | non_coding_transcript_exon_variant | 2/4 | 3 | ||||
COL1A2 | ENST00000481570.5 | n.2816G>A | non_coding_transcript_exon_variant | 3/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249302Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134770
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461382Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 726938
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74472
ClinVar
Submissions by phenotype
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;C5436847:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2;CN293783:Ehlers-danlos syndrome, arthrochalasia type, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 05, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 948 of the COL1A2 protein (p.Arg948His). This variant is present in population databases (rs201168934, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 526887). 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 expected to disrupt COL1A2 protein function. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2024 | The p.R948H variant (also known as c.2843G>A), located in coding exon 44 of the COL1A2 gene, results from a G to A substitution at nucleotide position 2843. The arginine at codon 948 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at