6-33164337-C-T

Position:

chr6-33164337-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_080680.3(COL11A2):c.5000G>A(p.Arg1667His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,612,916 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1667S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 14 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 0.456

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 -12 ACMG points.

PP2

Missense variant where missense usually causes diseases, COL11A2

BP4

Computational evidence support a benign effect (MetaRNN=0.014077336).

BP6

Variant 6-33164337-C-T is Benign according to our data. Variant chr6-33164337-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178321.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=9, Benign=2}. Variant chr6-33164337-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00116 (176/152286) while in subpopulation SAS AF= 0.00559 (27/4826). AF 95% confidence interval is 0.00395. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3 linkuse as main transcript	c.5000G>A	p.Arg1667His	missense_variant	65/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL11A2	ENST00000341947.7 linkuse as main transcript	c.5000G>A	p.Arg1667His	missense_variant	65/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8 linkuse as main transcript	c.4742G>A	p.Arg1581His	missense_variant	63/64	5		A1
COL11A2	ENST00000477772.1 linkuse as main transcript	n.790G>A		non_coding_transcript_exon_variant	8/9	2
COL11A2	ENST00000683572.1 linkuse as main transcript	n.806G>A		non_coding_transcript_exon_variant	8/9

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00191

AC:

469

AN:

246086

Hom.:

AF XY:

0.00225

AC XY:

302

AN XY:

134180

show subpopulations

Gnomad AFR exome

AF:

0.0000664

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00181

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00590

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00126

AC:

1845

AN:

1460630

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1060

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00618

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.000929

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152286

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00123

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00148

AC:

ExAC

AF:

0.00201

AC:

237

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	COL11A2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 23, 2015	p.Arg1667His in exon 65 of COL11A2: This variant is not expected to have clinica l significance because it has been identified in 0.18% (111/62708) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs146555195). In addition, it has been seen by our laboratory in two individuals with hearing loss, neither of whom carried a clinically significant COL11A2 variant on the other allele and both of whom had an alternate genetic e xplanation for their hearing loss. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 53

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Aug 06, 2018

This variant was identified in compound heterozygosity with a second variant in COL11A2 in a female patient with prelingual bilateral moderate hearing loss. -

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

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 01, 2018

- -

Stickler Syndrome, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fibrochondrogenesis 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.024

T;T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.32

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

-0.18

MutationTaster

Benign

0.97

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.29

Sift

Uncertain

0.028

D;D;D

Sift4G

Benign

0.12

T;T;T

Vest4

0.26

MVP

0.72

MPC

0.42

ClinPred

0.011

GERP RS

4.9

gMVP

0.62

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