6-33185751-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_080680.3(COL11A2):c.826G>A(p.Glu276Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,340,386 control chromosomes in the GnomAD database, including 67,232 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.33 ( 7530 hom., cov: 24)

Exomes 𝑓: 0.31 ( 59702 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.22

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024698675).

BP6

Variant 6-33185751-C-T is Benign according to our data. Variant chr6-33185751-C-T is described in ClinVar as [Benign]. Clinvar id is 46569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33185751-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3 link	c.826G>A	p.Glu276Lys	missense_variant	Exon 6 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.826G>A	p.Glu276Lys	missense_variant	Exon 6 of 66	5	NM_080680.3	ENSP00000339915.2	A0A0C4DFS1
COL11A2	ENST00000374708.8 link	c.799-697G>A		intron_variant	Intron 5 of 63	5		ENSP00000363840.4	Q4VXY6
COL11A2	ENST00000682718.1 link	n.643G>A		non_coding_transcript_exon_variant	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

46741

AN:

141668

Hom.:

7527

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.382

Gnomad EAS

AF:

0.236

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.343

GnomAD3 exomes

AF:

0.297

AC:

73141

AN:

246010

Hom.:

11550

AF XY:

0.306

AC XY:

41075

AN XY:

134128

show subpopulations

Gnomad AFR exome

AF:

0.367

Gnomad AMR exome

AF:

0.195

Gnomad ASJ exome

AF:

0.372

Gnomad EAS exome

AF:

0.238

Gnomad SAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.313

Gnomad OTH exome

AF:

0.310

GnomAD4 exome

AF:

0.311

AC:

372581

AN:

1198634

Hom.:

59702

Cov.:

AF XY:

0.315

AC XY:

187391

AN XY:

594858

show subpopulations

Gnomad4 AFR exome

AF:

0.390

Gnomad4 AMR exome

AF:

0.197

Gnomad4 ASJ exome

AF:

0.374

Gnomad4 EAS exome

AF:

0.242

Gnomad4 SAS exome

AF:

0.387

Gnomad4 FIN exome

AF:

0.220

Gnomad4 NFE exome

AF:

0.309

Gnomad4 OTH exome

AF:

0.313

GnomAD4 genome

AF:

0.330

AC:

46758

AN:

141752

Hom.:

7530

Cov.:

AF XY:

0.329

AC XY:

22398

AN XY:

68050

show subpopulations

Gnomad4 AFR

AF:

0.380

Gnomad4 AMR

AF:

0.298

Gnomad4 ASJ

AF:

0.382

Gnomad4 EAS

AF:

0.235

Gnomad4 SAS

AF:

0.387

Gnomad4 FIN

AF:

0.245

Gnomad4 NFE

AF:

0.317

Gnomad4 OTH

AF:

0.341

Alfa

AF:

0.311

Hom.:

12253

Bravo

AF:

0.318

TwinsUK

AF:

0.315

AC:

1168

ALSPAC

AF:

0.308

AC:

1186

ESP6500AA

AF:

0.367

AC:

1108

ESP6500EA

AF:

0.314

AC:

1703

ExAC

AF:

0.302

AC:

35411

Asia WGS

AF:

0.328

AC:

1141

AN:

3478

EpiCase

AF:

0.315

EpiControl

AF:

0.330

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu276Lys in Exon 06 of COL11A2: This variant is not expected to have clinical s ignificance because it has been identified in 36.5% (1108/3032) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs9277934). -

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fibrochondrogenesis 2

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 53

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 13

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stickler Syndrome, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

0.058

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.91

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.52

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.85

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.66

T;T

Sift4G

Benign

0.75

T;T

Vest4

0.17

ClinPred

0.019

GERP RS

3.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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