6-33173698-C-T

Position:

• chr6-33173698-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080680.3(COL11A2):​c.2628+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,565,514 control chromosomes in the GnomAD database, including 254,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26065 hom., cov: 28)
  • Exomes 𝑓: 0.56 (228645 hom.)
• Consequence: COL11A2 NM_080680.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001475
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.23

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-33173698-C-T is Benign according to our data. Variant chr6-33173698-C-T is described in ClinVar as [Benign]. Clinvar id is 46560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33173698-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.2628+3G>A		splice_region_variant, intron_variant		ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.2628+3G>A		splice_region_variant, intron_variant		5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.2370+3G>A		splice_region_variant, intron_variant		5		ENSP00000363840.4
COL11A2	ENST00000361917.6	c.1200+3G>A		splice_region_variant, intron_variant		5		ENSP00000355123.2
COL11A2	ENST00000477772.1	n.272+3311G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88095 AN: 150868 Hom.: 26050 Cov.: 28

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.607

GnomAD3 exomes AF: 0.604 AC: 127922 AN: 211774 Hom.: 39475 AF XY: 0.601 AC XY: 68694 AN XY: 114232

Gnomad AFR exome AF: 0.599

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.673

Gnomad EAS exome AF: 0.809

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.548

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.565 AC: 798514 AN: 1414528 Hom.: 228645 Cov.: 39 AF XY: 0.567 AC XY: 395908 AN XY: 698330

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.683

Gnomad4 ASJ exome AF: 0.671

Gnomad4 EAS exome AF: 0.833

Gnomad4 SAS exome AF: 0.629

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.567

GnomAD4 genome AF: 0.584 AC: 88142 AN: 150986 Hom.: 26065 Cov.: 28 AF XY: 0.584 AC XY: 43039 AN XY: 73742

Gnomad4 AFR AF: 0.595

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.675

Gnomad4 EAS AF: 0.788

Gnomad4 SAS AF: 0.633

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.550

Gnomad4 OTH AF: 0.610

Alfa AF: 0.578 Hom.: 20219

Bravo AF: 0.595

Asia WGS AF: 0.677 AC: 2357 AN: 3478

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	2628+3G>A in Intron 35 of COL11A2: This variant is not expected to have clinical significance because it has been identified in 44.8% (1993/4452) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs970901). -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -

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 03, 2025

- -

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	-0.48
CADD	Benign	21
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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: rs970901; hg19: chr6-33141475;