rs534570825
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS1
The NM_080680.3(COL11A2):c.3725C>T(p.Ser1242Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,612,882 control chromosomes in the GnomAD database, including 1 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 Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL11A2 | NM_080680.3 | c.3725C>T | p.Ser1242Leu | missense_variant | Exon 51 of 66 | ENST00000341947.7 | NP_542411.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL11A2 | ENST00000341947.7 | c.3725C>T | p.Ser1242Leu | missense_variant | Exon 51 of 66 | 5 | NM_080680.3 | ENSP00000339915.2 | ||
COL11A2 | ENST00000374708.8 | c.3467C>T | p.Ser1156Leu | missense_variant | Exon 49 of 64 | 5 | ENSP00000363840.4 | |||
COL11A2 | ENST00000477772.1 | n.273-3640C>T | intron_variant | Intron 5 of 8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152096Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000134 AC: 33AN: 246426Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 134338
GnomAD4 exome AF: 0.0000856 AC: 125AN: 1460668Hom.: 1 Cov.: 33 AF XY: 0.0000895 AC XY: 65AN XY: 726662
GnomAD4 genome AF: 0.000171 AC: 26AN: 152214Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12AN XY: 74430
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: COL11A2 c.3725C>T (p.Ser1242Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 1612882 control chromosomes, predominantly at a frequency of 0.00036 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. c.3725C>T has been reported in the literature in at least an individual affected with hearing loss (example: Ma_2023). This report does 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 publication has been ascertained in the context of this evaluation (PMID: 36597107). ClinVar contains an entry for this variant (Variation ID: 356389). Based on the evidence outlined above, the variant was classified as uncertain significance. -
The p.Ser1242Leu variant in COL11A2 has been previously reported by our laborato ry in one individual with hearing loss due to an alternate etiology. It has also been reported in ClinVar (Variation ID#356389) as likely benign in individuals of unknown clinical status. This variant has been identified in 34/271854 total chromosomes across several populations by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org; dbSNP rs534570825). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, the clinical significance of the p.Ser1242Leu variant is uncertain. ACMG/AMP Criteria applied: BP5, PM2_P (Richards 2015). -
not provided Uncertain:1Benign:1
Reported in a patient with hearing loss in published literature (PMID: 36597107); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36597107) -
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Inborn genetic diseases Uncertain:1
The c.3725C>T (p.S1242L) alteration is located in exon 51 (coding exon 51) of the COL11A2 gene. This alteration results from a C to T substitution at nucleotide position 3725, causing the serine (S) at amino acid position 1242 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Otospondylomegaepiphyseal dysplasia, autosomal recessive Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Fibrochondrogenesis 2 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1
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Stickler Syndrome, Dominant Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at