rs145499142
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_080680.3(COL11A2):c.1615C>T(p.Arg539Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,052 control chromosomes in the GnomAD database, including 12 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_080680.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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COL11A2 | NM_080680.3 | c.1615C>T | p.Arg539Trp | missense_variant | Exon 17 of 66 | ENST00000341947.7 | NP_542411.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL11A2 | ENST00000341947.7 | c.1615C>T | p.Arg539Trp | missense_variant | Exon 17 of 66 | 5 | NM_080680.3 | ENSP00000339915.2 | ||
COL11A2 | ENST00000374708.8 | c.1357C>T | p.Arg453Trp | missense_variant | Exon 15 of 64 | 5 | ENSP00000363840.4 | |||
COL11A2 | ENST00000361917.6 | c.241C>T | p.Arg81Trp | missense_variant | Exon 5 of 24 | 5 | ENSP00000355123.2 |
Frequencies
GnomAD3 genomes AF: 0.00155 AC: 236AN: 152092Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00116 AC: 290AN: 250410Hom.: 2 AF XY: 0.00114 AC XY: 154AN XY: 135570
GnomAD4 exome AF: 0.00255 AC: 3727AN: 1461842Hom.: 11 Cov.: 35 AF XY: 0.00245 AC XY: 1785AN XY: 727224
GnomAD4 genome AF: 0.00155 AC: 236AN: 152210Hom.: 1 Cov.: 32 AF XY: 0.00137 AC XY: 102AN XY: 74444
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4Other:1
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GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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COL11A2: BS2 -
not specified Uncertain:2Benign:1
p.Arg539Trp in exon 17 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 0.2% (250/126012) European chrom osomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs145499142). Although it has been reported in one individual with Stickler syndrome and seven individuals with hearing los s (Acke 2014, LMM data), four of these individuals were found to have an alterna te genetic etiology. Furthermore, the variant was identified in one family with early onset osteoarthritis, but one affected family member was negative for the variant and one individual who carried the variant did not have disease (Jakkul a 2005). -
A published variant of uncertain significance has been identified in the COL11A2 gene. The R539W variant was first reported in a 38-year-old Finnish individual with early-onset osteoarthritis (OA) and segregated with OA in three affected relatives (Jakkula et al., 2005). However, in this same family, R539W was found in a 45-year-old relative without OA and was absent from a 65-year-old relative with OA, although the age of onset in this relative was reportedly much later than other affected relatives (Jakkula et al., 2005). The R539W variant has also been reported in one Belgian individual with type 3 Stickler syndrome who had hearing loss and both a personal and family history of skeletal features of this condition (Acke et al., 2014); however, no segregation studies were described. More recently, this variant, reported as R453W due to the use of an alternate transcript, was identified in at least one Western European individual with presumed autosomal recessive non-syndromic hearing loss (Sommen et al., 2016), although further clinical or segregation data was not available. The R539W variant was observed at a frequency of approximately 0.16-0.28% of alleles from individuals of European ancestry, including one homozygous individual, in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). Nevertheless, R539W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. -
Variant summary: COL11A2 c.1615C>T (p.Arg539Trp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of 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 0.0012 in 250410 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. c.1615C>T has been reported in the literature in 4 siblings with confirmed early onset osteoarthritis. However, it was also detected in one family member with no radiological evidence of osteoarthritis, and was absent from another family member with osteoarthritis (Jakkula_2005). Furthermore, the variant has been reported in individuals affected with nonsyndromic hearing loss and Stickler syndrome, without strong evidence of causality (Acke_2014, Sommen_2016), as well as a patient with an unspecified connective tissue disorer (Steinle_2022). These reports do not provide unequivocal conclusions about association of the variant with COL11A2-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25240749, 27068579, 15922184, 35903967). ClinVar contains an entry for this variant (Variation ID: 46556). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Otospondylomegaepiphyseal dysplasia, autosomal recessive 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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Connective tissue disorder Uncertain:1
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Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1
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Stickler Syndrome, Dominant Benign:1
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Fibrochondrogenesis 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at