rs139851311
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_000089.4(COL1A2):c.3313G>A(p.Gly1105Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,106 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000089.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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COL1A2 | NM_000089.4 | c.3313G>A | p.Gly1105Ser | missense_variant | Exon 49 of 52 | ENST00000297268.11 | NP_000080.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.3313G>A | p.Gly1105Ser | missense_variant | Exon 49 of 52 | 1 | NM_000089.4 | ENSP00000297268.6 | ||
COL1A2 | ENST00000464916.1 | n.361G>A | non_coding_transcript_exon_variant | Exon 1 of 4 | 2 | |||||
COL1A2 | ENST00000481570.5 | n.4094G>A | non_coding_transcript_exon_variant | Exon 6 of 8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000717 AC: 109AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000995 AC: 250AN: 251270Hom.: 0 AF XY: 0.00101 AC XY: 137AN XY: 135800
GnomAD4 exome AF: 0.00127 AC: 1857AN: 1461870Hom.: 5 Cov.: 33 AF XY: 0.00131 AC XY: 950AN XY: 727238
GnomAD4 genome AF: 0.000716 AC: 109AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.000739 AC XY: 55AN XY: 74436
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
The COL1A2 c.3313G>A; p.Gly1105Ser variant (rs139851311; ClinVar Variation ID: 360968) is reported in the literature in several individuals affected with osteogenesis imperfecta or Ehlers-Danlos Syndrome, though it was not demonstrated to cause disease (Junkiert-Czarnecka 2022, Lin 2024, Mei 2022, Stephen 2014, Zhang 2012). This variant is found in the South Asian population with an overall allele frequency of 0.24% (73/30610 alleles) in the Genome Aggregation Database (v2.1.1). The glycine at codon 1105 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.783). It is unclear if this glycine residue is incorporated into the collagen triple helix domain. While the population frequency of this variant is inconsistent with disease, given the lack of clinical and functional data, the significance of the p.Gly1105Ser variant is uncertain at this time. References: Junkiert-Czarnecka A et al. Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome. Curr Issues Mol Biol. 2022 Mar 25;44(4):1472-1478. PMID: 35723357. Lin X et al. Genotype-phenotype relationship and comparison between eastern and western patients with osteogenesis imperfecta. J Endocrinol Invest. 2024 Jan;47(1):67-77. PMID: 37270749. Mei Y et al. Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. PMID: 35909573. Stephen J et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. Am J Med Genet A. 2014 Jun;164A(6):1482-9. PMID: 24668929. Zhang ZL et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J Bone Miner Metab. 2012 Jan;30(1):69-77. PMID: 21667357. -
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COL1A2: BS1 -
not specified Benign:2
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: COL1A2 c.3313G>A (p.Gly1105Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 251270 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 85.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Osteogenesis Imperfecta phenotype (2.8e-05). c.3313G>A has been reported in the literature in heterozygous individuals affected with Osteogenesis Imperfecta (Mrosk_2018, Zhang_2012). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (COL1A1 c.2299G>A , p.Gly767Ser), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 360968). Based on the evidence outlined above, the variant was classified as likely benign. -
Osteogenesis imperfecta Benign:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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Ehlers-Danlos syndrome Uncertain:1
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Connective tissue disorder Uncertain:1
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Ehlers-danlos syndrome, arthrochalasia type, 2 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at