rs2229792

Positions:

chr6-33163724-G-A

Variant summary

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

The NM_080680.3(COL11A2):c.5165C>T(p.Pro1722Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,613,068 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. P1722P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 69 hom., cov: 32)

Exomes 𝑓: 0.020 ( 466 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.801

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 -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=0.0019938052).

BP6

Variant 6-33163724-G-A is Benign according to our data. Variant chr6-33163724-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 46568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33163724-G-A is described in Lovd as [Benign]. Variant chr6-33163724-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0185 (2813/152296) while in subpopulation NFE AF= 0.0244 (1659/68010). AF 95% confidence interval is 0.0234. There are 69 homozygotes in gnomad4. There are 1349 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 69 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.5165C>T	p.Pro1722Leu	missense_variant	66/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL11A2	ENST00000341947.7 linkuse as main transcript	c.5165C>T	p.Pro1722Leu	missense_variant	66/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8 linkuse as main transcript	c.4907C>T	p.Pro1636Leu	missense_variant	64/64	5		A1
COL11A2	ENST00000477772.1 linkuse as main transcript	n.955C>T		non_coding_transcript_exon_variant	9/9	2
COL11A2	ENST00000683572.1 linkuse as main transcript	n.971C>T		non_coding_transcript_exon_variant	9/9

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2813

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0203

AC:

4962

AN:

244856

Hom.:

108

AF XY:

0.0202

AC XY:

2699

AN XY:

133620

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.00148

Gnomad SAS exome

AF:

0.00807

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0197

AC:

28847

AN:

1460772

Hom.:

466

Cov.:

AF XY:

0.0201

AC XY:

14627

AN XY:

726704

show subpopulations

Gnomad4 AFR exome

AF:

0.00349

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.105

Gnomad4 EAS exome

AF:

0.000806

Gnomad4 SAS exome

AF:

0.00872

Gnomad4 FIN exome

AF:

0.0216

Gnomad4 NFE exome

AF:

0.0197

Gnomad4 OTH exome

AF:

0.0237

GnomAD4 genome

AF:

0.0185

AC:

2813

AN:

152296

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1349

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00274

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.119

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00808

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.0244

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0260

Hom.:

149

Bravo

AF:

0.0170

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00298

AC:

ESP6500EA

AF:

0.0255

AC:

138

ExAC

AF:

0.0191

AC:

2262

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0252

EpiControl

AF:

0.0231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro1722Leu in Exon 66 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 2.6% (117/4486) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2229792). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 12, 2022

- -

Fibrochondrogenesis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Stickler Syndrome, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

T;T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.18

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.017

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Vest4

0.15

MPC

0.34

ClinPred

0.023

GERP RS

4.1

gMVP

0.49

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