rs1799908

chr6-33176466-T-Achr6-33176466-T-Cchr6-33176466-T-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.2136A>T(p.Gly712=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 1,610,068 control chromosomes in the GnomAD database, including 155,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G712G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17184 hom., cov: 30)
  • Exomes 𝑓: 0.43 (138701 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.197

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=-0.5).
• BP6: Variant 6-33176466-T-A is Benign according to our data. Variant chr6-33176466-T-A is described in ClinVar as [Benign]. Clinvar id is 46558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33176466-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.197 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.2136A>T	p.Gly712=	synonymous_variant	27/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.2136A>T	p.Gly712=	synonymous_variant	27/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.1878A>T	p.Gly626=	synonymous_variant	25/64	5		A1
COL11A2	ENST00000361917.6	c.711A>T	p.Gly237=	synonymous_variant	14/24	5
COL11A2	ENST00000477772.1	n.272+543A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.468 AC: 70966 AN: 151620 Hom.: 17155 Cov.: 30

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.485 AC: 119248 AN: 245818 Hom.: 30455 AF XY: 0.477 AC XY: 63941 AN XY: 133936

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.739

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.429 AC: 625325 AN: 1458330 Hom.: 138701 Cov.: 45 AF XY: 0.430 AC XY: 312167 AN XY: 725548

Gnomad4 AFR exome AF: 0.497

Gnomad4 AMR exome AF: 0.594

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.752

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.482

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.468 AC: 71048 AN: 151738 Hom.: 17184 Cov.: 30 AF XY: 0.475 AC XY: 35190 AN XY: 74100

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.520

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.505

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.479

Alfa AF: 0.419 Hom.: 10435

Bravo AF: 0.476

Asia WGS AF: 0.572 AC: 1988 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.410

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly712Gly in Exon 27 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 49.7% (1508/3036) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1799908). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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+	-	- -
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. -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:2

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

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:2

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

Fibrochondrogenesis 2 Benign:2

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

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

Invitae

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	-0.50
Cadd	Benign	9.4
Dann	Benign	0.76

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

Other links and lift over

dbSNP: rs1799908; hg19: chr6-33144243; COSMIC: COSV59497779; COSMIC: COSV59497779;