rs145499142

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_080680.3(COL11A2):c.1615C>T(p.Arg539Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,052 control chromosomes in the GnomAD database, including 12 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

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 11 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:10O:1

Conservation

PhyloP100: 3.20

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 Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17189929).

BP6

Variant 6-33178970-G-A is Benign according to our data. Variant chr6-33178970-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46556.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=4, not_provided=1}. Variant chr6-33178970-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00155 (236/152210) while in subpopulation NFE AF= 0.00269 (183/67982). AF 95% confidence interval is 0.00237. There are 1 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3 link	c.1615C>T	p.Arg539Trp	missense_variant	Exon 17 of 66	ENST00000341947.7	NP_542411.2	P13942A0A0C4DFS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL11A2	ENST00000341947.7 link	c.1615C>T	p.Arg539Trp	missense_variant	Exon 17 of 66	5	NM_080680.3	ENSP00000339915.2	A0A0C4DFS1
COL11A2	ENST00000374708.8 link	c.1357C>T	p.Arg453Trp	missense_variant	Exon 15 of 64	5		ENSP00000363840.4	Q4VXY6
COL11A2	ENST00000361917.6 link	c.241C>T	p.Arg81Trp	missense_variant	Exon 5 of 24	5		ENSP00000355123.2	H0YIS1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00116

AC:

290

AN:

250410

Hom.:

AF XY:

0.00114

AC XY:

154

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.000373

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.00255

AC:

3727

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00245

AC XY:

1785

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00137

Gnomad4 NFE exome

AF:

0.00311

Gnomad4 OTH exome

AF:

0.00247

GnomAD4 genome

AF:

0.00155

AC:

236

AN:

152210

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00269

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00165

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00277

AC:

ExAC

AF:

0.00104

AC:

126

EpiCase

AF:

0.00196

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4Other:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL11A2: BS1, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:2Benign:1

May 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg539Trp in exon 17 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 0.2% (250/126012) European chrom osomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs145499142). Although it has been reported in one individual with Stickler syndrome and seven individuals with hearing los s (Acke 2014, LMM data), four of these individuals were found to have an alterna te genetic etiology. Furthermore, the variant was identified in one family with early onset osteoarthritis, but one affected family member was negative for the variant and one individual who carried the variant did not have disease (Jakkul a 2005). -

May 31, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A published variant of uncertain significance has been identified in the COL11A2 gene. The R539W variant was first reported in a 38-year-old Finnish individual with early-onset osteoarthritis (OA) and segregated with OA in three affected relatives (Jakkula et al., 2005). However, in this same family, R539W was found in a 45-year-old relative without OA and was absent from a 65-year-old relative with OA, although the age of onset in this relative was reportedly much later than other affected relatives (Jakkula et al., 2005). The R539W variant has also been reported in one Belgian individual with type 3 Stickler syndrome who had hearing loss and both a personal and family history of skeletal features of this condition (Acke et al., 2014); however, no segregation studies were described. More recently, this variant, reported as R453W due to the use of an alternate transcript, was identified in at least one Western European individual with presumed autosomal recessive non-syndromic hearing loss (Sommen et al., 2016), although further clinical or segregation data was not available. The R539W variant was observed at a frequency of approximately 0.16-0.28% of alleles from individuals of European ancestry, including one homozygous individual, in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). Nevertheless, R539W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. -

Sep 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL11A2 c.1615C>T (p.Arg539Trp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 250410 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. c.1615C>T has been reported in the literature in 4 siblings with confirmed early onset osteoarthritis. However, it was also detected in one family member with no radiological evidence of osteoarthritis, and was absent from another family member with osteoarthritis (Jakkula_2005). Furthermore, the variant has been reported in individuals affected with nonsyndromic hearing loss and Stickler syndrome, without strong evidence of causality (Acke_2014, Sommen_2016), as well as a patient with an unspecified connective tissue disorer (Steinle_2022). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 25240749, 27068579, 15922184, 35903967). ClinVar contains an entry for this variant (Variation ID: 46556). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Otospondylomegaepiphyseal dysplasia, autosomal recessive

Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Connective tissue disorder

Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stickler Syndrome, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibrochondrogenesis 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;T;.;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.17

T;T;T;T

MetaSVM

Benign

-0.75

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.8

D;D;D;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Vest4

0.69

MVP

0.66

MPC

1.1

ClinPred

0.15

GERP RS

3.6

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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