6-33178143-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PS1_ModeratePP5BS1_Supporting
The NM_080680.3(COL11A2):c.1861C>A(p.Pro621Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000888 in 1,609,686 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_080680.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL11A2 | NM_080680.3 | c.1861C>A | p.Pro621Thr | missense_variant | Exon 21 of 66 | ENST00000341947.7 | NP_542411.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL11A2 | ENST00000341947.7 | c.1861C>A | p.Pro621Thr | missense_variant | Exon 21 of 66 | 5 | NM_080680.3 | ENSP00000339915.2 | ||
COL11A2 | ENST00000374708.8 | c.1603C>A | p.Pro535Thr | missense_variant | Exon 19 of 64 | 5 | ENSP00000363840.4 | |||
COL11A2 | ENST00000361917.6 | c.444+165C>A | intron_variant | Intron 8 of 23 | 5 | ENSP00000355123.2 | ||||
COL11A2 | ENST00000477772.1 | n.-250C>A | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000527 AC: 8AN: 151868Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000899 AC: 22AN: 244724Hom.: 0 AF XY: 0.000135 AC XY: 18AN XY: 133324
GnomAD4 exome AF: 0.0000926 AC: 135AN: 1457818Hom.: 1 Cov.: 34 AF XY: 0.000101 AC XY: 73AN XY: 724838
GnomAD4 genome AF: 0.0000527 AC: 8AN: 151868Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74168
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 621 of the COL11A2 protein (p.Pro621Thr). This variant is present in population databases (rs121912952, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 16033917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL11A2 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Reported in the homozygous state in five relatives from a consanguineous family with non-syndromic hearing loss (PMID: 16033917); 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: 34426522, 16033917) -
COL11A2: PP1:Strong, PM2 -
Autosomal recessive nonsyndromic hearing loss 53 Pathogenic:1Uncertain:1
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Otospondylomegaepiphyseal dysplasia, autosomal dominant;C1864746:Autosomal recessive nonsyndromic hearing loss 53;C1866095:Autosomal dominant nonsyndromic hearing loss 13;C3281128:Fibrochondrogenesis 2;C5551484:Otospondylomegaepiphyseal dysplasia, autosomal recessive Pathogenic:1
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not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro621Thr variant in COL11A2 has been reported in the homozygous state in one Iranian ind ividual with hearing loss and segregated with disease in 4 affected relatives wi thin the individual's consanguineous family (Chen 2005). This variant has also b een identified in 10/14172 South Asian chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121912952). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that the p.Pro621Thr variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. However, there is limited data associating variants in the COL11A2 gene wit h autosomal recessive nonsyndromic hearing loss. Only three consanguineous famil ies with homozygous variants in COL11A2 have been described, including the famil y described above with the p.Pro621THr variant. In addition, there is limited da ta of the general populations from which these families are from (Iranian, Tunis ian, and Turkish; Chen 2005, Chakchouk 2015). In summary, although there is some suspicion for a pathogenic role, the clinical significance of this variant is u ncertain. -
Hearing impairment Uncertain:1
PS1_Moderate, PM2_Moderate -
Fibrochondrogenesis 2 Uncertain:1
A heterozygous variant in exon 21 of the COL11A2 gene that results in the amino acid substitution of Threonine for Prolin at codon 621 was detected. The observed variant c.1861C>A (p.Pro621Thr) has not found in the 1000 genomes and has minor allele frequency of 0.008% and 0.005% in the gnomAD (V2.1) and gnomAD (V3.1) databases respectively. The in silico prediction of the variant is probably damaging by PolyPhen-2, SIFT, LRT and MutationTaster2. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at