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

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000093 ( 1 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

4
7
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 1.03
Variant links:
Genes affected
COL11A2 (HGNC:2187): (collagen type XI alpha 2 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PS1
Transcript NM_080680.3 (COL11A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PP5
Variant 6-33178143-G-T is Pathogenic according to our data. Variant chr6-33178143-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17129.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=5, Pathogenic=2}. Variant chr6-33178143-G-T is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000926 (135/1457818) while in subpopulation MID AF= 0.000696 (4/5750). AF 95% confidence interval is 0.000422. There are 1 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL11A2NM_080680.3 linkc.1861C>A p.Pro621Thr missense_variant Exon 21 of 66 ENST00000341947.7 NP_542411.2 P13942A0A0C4DFS1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL11A2ENST00000341947.7 linkc.1861C>A p.Pro621Thr missense_variant Exon 21 of 66 5 NM_080680.3 ENSP00000339915.2 A0A0C4DFS1
COL11A2ENST00000374708.8 linkc.1603C>A p.Pro535Thr missense_variant Exon 19 of 64 5 ENSP00000363840.4 Q4VXY6
COL11A2ENST00000361917.6 linkc.444+165C>A intron_variant Intron 8 of 23 5 ENSP00000355123.2 H0YIS1
COL11A2ENST00000477772.1 linkn.-250C>A upstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000527
AC:
8
AN:
151868
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000899
AC:
22
AN:
244724
Hom.:
0
AF XY:
0.000135
AC XY:
18
AN XY:
133324
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000433
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000819
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000926
AC:
135
AN:
1457818
Hom.:
1
Cov.:
34
AF XY:
0.000101
AC XY:
73
AN XY:
724838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000547
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000676
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000527
AC:
8
AN:
151868
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74168
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000947
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.000135
AC:
16

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:1
Sep 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 16, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

May 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL11A2: PP1:Strong, PM2 -

Autosomal recessive nonsyndromic hearing loss 53 Pathogenic:1Uncertain:1
Feb 01, 2022
MGZ Medical Genetics Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2005
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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
Apr 02, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Mar 08, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Apr 12, 2021
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS1_Moderate, PM2_Moderate -

Fibrochondrogenesis 2 Uncertain:1
Sep 24, 2024
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Uncertain
0.047
T
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.077
T;T;.;D
Eigen
Benign
-0.069
Eigen_PC
Benign
-0.034
FATHMM_MKL
Uncertain
0.78
D
M_CAP
Pathogenic
0.32
D
MetaRNN
Uncertain
0.48
T;T;T;T
MetaSVM
Uncertain
0.75
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-4.5
D;D;D;D
REVEL
Pathogenic
0.73
Sift
Benign
0.091
T;T;T;T
Sift4G
Uncertain
0.058
T;T;T;D
Vest4
0.52
MutPred
0.73
.;Gain of phosphorylation at P621 (P = 0.0056);.;Gain of phosphorylation at P621 (P = 0.0056);
MVP
0.93
MPC
0.99
ClinPred
0.26
T
GERP RS
4.3
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912952; hg19: chr6-33145920; COSMIC: COSV59500310; COSMIC: COSV59500310; API