chr6-33189068-C-G

Position:

chr6-33189068-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_080680.3(COL11A2):c.353G>C(p.Arg118Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,162 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.74

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:

COL11A2 (HGNC:):

COL11A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.014154375).

BP6

Variant 6-33189068-C-G is Benign according to our data. Variant chr6-33189068-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 162997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33189068-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00148 (225/152270) while in subpopulation NFE AF= 0.00231 (157/68004). AF 95% confidence interval is 0.00201. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.353G>C	p.Arg118Pro	missense_variant	3/66	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.353G>C	p.Arg118Pro	missense_variant	3/66	5	NM_080680.3	ENSP00000339915.2	A0A0C4DFS1
COL11A2	ENST00000395194.1 linkuse as main transcript	c.353G>C	p.Arg118Pro	missense_variant	3/5	1		ENSP00000378620.1	P13942-9
COL11A2	ENST00000374708.8 linkuse as main transcript	c.353G>C	p.Arg118Pro	missense_variant	3/64	5		ENSP00000363840.4	Q4VXY6
COL11A2	ENST00000682718.1 linkuse as main transcript	n.170G>C		non_coding_transcript_exon_variant	2/6

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00208

AC:

523

AN:

251378

Hom.:

AF XY:

0.00208

AC XY:

283

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.00314

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00155

AC:

2272

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1132

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00376

Gnomad4 NFE exome

AF:

0.00167

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152270

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00222

AC:

269

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COL11A2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	This variant is associated with the following publications: (PMID: 23804846, 27068579, 24036952, 28839234) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2015	p.Arg118Pro in exon 3 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 0.3% (225/66582) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs41268014). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Stickler Syndrome, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

Fibrochondrogenesis 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;T;.;T;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.036

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.3

.;.;.;.;L

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.3

D;D;D;D;D

REVEL

Benign

0.24

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.078

T;T;T;T;D

Vest4

0.58

MVP

0.44

MPC

1.1

ClinPred

0.044

GERP RS

2.6

gMVP

0.71

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