6-33173384-A-G

Position:

• chr6-33173384-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_080680.3(COL11A2):​c.2700T>C​(p.Asp900=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,612,256 control chromosomes in the GnomAD database, including 459,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48107 hom., cov: 31)
  • Exomes 𝑓: 0.75 (411098 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -3.21

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-33173384-A-G is Benign according to our data. Variant chr6-33173384-A-G is described in ClinVar as [Benign]. Clinvar id is 46562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33173384-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.2700T>C	p.Asp900=	synonymous_variant	37/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.2700T>C	p.Asp900=	synonymous_variant	37/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.2442T>C	p.Asp814=	synonymous_variant	35/64	5		A1
COL11A2	ENST00000361917.6	c.1275T>C	p.Asp425=	synonymous_variant	24/24	5
COL11A2	ENST00000477772.1	n.272+3625T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.791 AC: 120141 AN: 151830 Hom.: 48058 Cov.: 31

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.805

GnomAD3 exomes AF: 0.790 AC: 192906 AN: 244044 Hom.: 77305 AF XY: 0.791 AC XY: 104814 AN XY: 132428

Gnomad AFR exome AF: 0.883

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.847

Gnomad EAS exome AF: 0.987

Gnomad SAS exome AF: 0.893

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.723

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.747 AC: 1091067 AN: 1460308 Hom.: 411098 Cov.: 63 AF XY: 0.752 AC XY: 545901 AN XY: 726396

Gnomad4 AFR exome AF: 0.888

Gnomad4 AMR exome AF: 0.808

Gnomad4 ASJ exome AF: 0.845

Gnomad4 EAS exome AF: 0.990

Gnomad4 SAS exome AF: 0.891

Gnomad4 FIN exome AF: 0.704

Gnomad4 NFE exome AF: 0.719

Gnomad4 OTH exome AF: 0.769

GnomAD4 genome AF: 0.791 AC: 120246 AN: 151948 Hom.: 48107 Cov.: 31 AF XY: 0.793 AC XY: 58862 AN XY: 74250

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.800

Gnomad4 ASJ AF: 0.837

Gnomad4 EAS AF: 0.983

Gnomad4 SAS AF: 0.906

Gnomad4 FIN AF: 0.713

Gnomad4 NFE AF: 0.726

Gnomad4 OTH AF: 0.807

Alfa AF: 0.729 Hom.: 4938

Bravo AF: 0.801

Asia WGS AF: 0.910 AC: 3163 AN: 3478

EpiCase AF: 0.739

EpiControl AF: 0.748

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asp900Asp in Exon 37 of COL11A2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 26.8% (1205/4488) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2229785). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Fibrochondrogenesis 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Autosomal recessive nonsyndromic hearing loss 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autosomal dominant nonsyndromic hearing loss 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.073
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2229785; hg19: chr6-33141161;