rs2855430

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_080680.3(COL11A2):c.2681C>T(p.Pro894Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,611,686 control chromosomes in the GnomAD database, including 14,943 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P894R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.10 ( 1012 hom., cov: 27)

Exomes 𝑓: 0.13 ( 13931 hom. )

Consequence

COL11A2
NM_080680.3 missense, splice_region

Scores

Splicing: ADA: 0.9241

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.76

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=0.0038810372).

BP6

Variant 6-33173503-G-A is Benign according to our data. Variant chr6-33173503-G-A is described in ClinVar as [Benign]. Clinvar id is 46561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33173503-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.2681C>T	p.Pro894Leu	missense_variant, splice_region_variant	36/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL11A2	ENST00000341947.7 linkuse as main transcript	c.2681C>T	p.Pro894Leu	missense_variant, splice_region_variant	36/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8 linkuse as main transcript	c.2423C>T	p.Pro808Leu	missense_variant, splice_region_variant	34/64	5		A1
COL11A2	ENST00000361917.6 linkuse as main transcript	c.1256C>T	p.Pro419Leu	missense_variant, splice_region_variant	23/24	5
COL11A2	ENST00000477772.1 linkuse as main transcript	n.272+3506C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15312

AN:

151370

Hom.:

1012

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0720

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.0819

GnomAD3 exomes

AF:

0.122

AC:

29605

AN:

243556

Hom.:

2149

AF XY:

0.127

AC XY:

16868

AN XY:

132338

show subpopulations

Gnomad AFR exome

AF:

0.0247

Gnomad AMR exome

AF:

0.0594

Gnomad ASJ exome

AF:

0.0889

Gnomad EAS exome

AF:

0.0966

Gnomad SAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.134

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.134

AC:

195391

AN:

1460200

Hom.:

13931

Cov.:

AF XY:

0.135

AC XY:

98184

AN XY:

726324

show subpopulations

Gnomad4 AFR exome

AF:

0.0239

Gnomad4 AMR exome

AF:

0.0600

Gnomad4 ASJ exome

AF:

0.0907

Gnomad4 EAS exome

AF:

0.112

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.178

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.124

GnomAD4 genome

AF:

0.101

AC:

15309

AN:

151486

Hom.:

1012

Cov.:

AF XY:

0.103

AC XY:

7638

AN XY:

73992

show subpopulations

Gnomad4 AFR

AF:

0.0275

Gnomad4 AMR

AF:

0.0720

Gnomad4 ASJ

AF:

0.0795

Gnomad4 EAS

AF:

0.108

Gnomad4 SAS

AF:

0.182

Gnomad4 FIN

AF:

0.179

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.0829

Alfa

AF:

0.125

Hom.:

2446

Bravo

AF:

0.0870

TwinsUK

AF:

0.140

AC:

518

ALSPAC

AF:

0.138

AC:

532

ESP6500AA

AF:

0.0273

AC:

120

ESP6500EA

AF:

0.131

AC:

1130

ExAC

AF:

0.122

AC:

14660

Asia WGS

AF:

0.117

AC:

405

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.120

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro894Leu in Exon 36 of COL11A2: This variant is not expected to have clinical s ignificance because it has been identified in 13.1% (919/7012) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2855430). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant

Benign:1

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 13, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fibrochondrogenesis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Stickler Syndrome, Dominant

Benign:1

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

0.099

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

T;T;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.81

MutationTaster

Benign

6.2e-11

P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.089

T;T;T

Sift4G

Uncertain

0.018

D;D;D

Vest4

0.36

MPC

0.99

ClinPred

0.029

GERP RS

4.0

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.85

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