rs121912952

Positions:

chr6-33178143-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_ModeratePP2PP5

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 same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

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

Exomes 𝑓: 0.000093 ( 1 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

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]

COL11A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PS1

Transcript NM_080680.3 (COL11A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL11A2. . Gene score misZ 2.3685 (greater than the threshold 3.09). Trascript score misZ 3.3886 (greater than threshold 3.09). GenCC has associacion of gene with otospondylomegaepiphyseal dysplasia, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss, autosomal recessive nonsyndromic hearing loss 53, otospondylomegaepiphyseal dysplasia, autosomal dominant, nonsyndromic genetic hearing loss, fibrochondrogenesis, hearing loss, autosomal recessive, otospondylomegaepiphyseal dysplasia, autosomal recessive.

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: {Uncertain_significance=5, Pathogenic=1, Likely_pathogenic=1}. Variant chr6-33178143-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.1861C>A	p.Pro621Thr	missense_variant	21/66	ENST00000341947.7	NP_542411.2	P13942A0A0C4DFS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL11A2	ENST00000341947.7 linkuse as main transcript	c.1861C>A	p.Pro621Thr	missense_variant	21/66	5	NM_080680.3	ENSP00000339915.2	A0A0C4DFS1
COL11A2	ENST00000374708.8 linkuse as main transcript	c.1603C>A	p.Pro535Thr	missense_variant	19/64	5		ENSP00000363840.4	Q4VXY6
COL11A2	ENST00000361917.6 linkuse as main transcript	c.444+165C>A		intron_variant		5		ENSP00000355123.2	H0YIS1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151868

Hom.:

Cov.:

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:

AN:

244724

Hom.:

AF XY:

0.000135

AC XY:

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.:

Cov.:

AF XY:

0.000101

AC XY:

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:

AN:

151868

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

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.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000135

AC:

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	COL11A2: PP1:Strong, PM2 -

Autosomal recessive nonsyndromic hearing loss 53

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 01, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 02, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 08, 2016

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

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Moderate, PM2_Moderate -

Fibrochondrogenesis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Sep 24, 2024

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

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

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

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Uncertain

0.75

PrimateAI

Uncertain

0.68

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over