6-33167508-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6
The NM_080680.3(COL11A2):c.4040C>T(p.Pro1347Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,612,610 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1347Q) has been classified as Likely benign.
Frequency
Consequence
NM_080680.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant nonsyndromic hearing loss 13Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
- nonsyndromic genetic hearing lossInheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
- otospondylomegaepiphyseal dysplasia, autosomal dominantInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
- autosomal recessive nonsyndromic hearing loss 53Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- otospondylomegaepiphyseal dysplasiaInheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- otospondylomegaepiphyseal dysplasia, autosomal recessiveInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- autosomal dominant nonsyndromic hearing lossInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- fibrochondrogenesisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL11A2 | NM_080680.3 | c.4040C>T | p.Pro1347Leu | missense_variant | Exon 56 of 66 | ENST00000341947.7 | NP_542411.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL11A2 | ENST00000341947.7 | c.4040C>T | p.Pro1347Leu | missense_variant | Exon 56 of 66 | 5 | NM_080680.3 | ENSP00000339915.2 | ||
COL11A2 | ENST00000374708.8 | c.3782C>T | p.Pro1261Leu | missense_variant | Exon 54 of 64 | 5 | ENSP00000363840.4 | |||
COL11A2 | ENST00000683572.1 | n.7C>T | non_coding_transcript_exon_variant | Exon 1 of 9 | ||||||
COL11A2 | ENST00000477772.1 | n.273-1692C>T | intron_variant | Intron 5 of 8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000827 AC: 20AN: 241766 AF XY: 0.0000529 show subpopulations
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1460504Hom.: 0 Cov.: 40 AF XY: 0.0000234 AC XY: 17AN XY: 726552 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -
Inborn genetic diseases Uncertain:1
The c.4040C>T (p.P1347L) alteration is located in exon 56 (coding exon 56) of the COL11A2 gene. This alteration results from a C to T substitution at nucleotide position 4040, causing the proline (P) at amino acid position 1347 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
COL11A2-related disorder Uncertain:1
The COL11A2 c.4040C>T variant is predicted to result in the amino acid substitution p.Pro1347Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Connective tissue disorder Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at