6-33164973-T-C

Variant names:

• chr6-33164973-T-C
• rs555680585
• NM_080680.3:c.4751-9A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_080680.3(COL11A2):​c.4751-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,564,354 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Scores: Splicing: ADA: 0.0001037
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -3.75
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 13

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive nonsyndromic hearing loss 53

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• otospondylomegaepiphyseal dysplasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-33164973-T-C is Benign according to our data. Variant chr6-33164973-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227272.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000467 (71/152152) while in subpopulation SAS AF = 0.0125 (60/4818). AF 95% confidence interval is 0.00993. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.4751-9A>G		intron_variant	Intron 63 of 65	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.4751-9A>G		intron_variant	Intron 63 of 65	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.4493-9A>G		intron_variant	Intron 61 of 63	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.541-9A>G		intron_variant	Intron 6 of 8	2
COL11A2	ENST00000683572.1	n.557-9A>G		intron_variant	Intron 6 of 8

Frequencies

GnomAD3 genomes AF: 0.000474 AC: 72 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000444 AC: 78 AN: 175742 AF XY: 0.000516

Gnomad AFR exome AF: 0.0000952

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00205

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000624

GnomAD4 exome AF: 0.000239 AC: 337 AN: 1412202 Hom.: 3 Cov.: 32 AF XY: 0.000347 AC XY: 242 AN XY: 698006

African (AFR) AF: 0.0000618 AC: 2 AN: 32386

American (AMR) AF: 0.00 AC: 0 AN: 37822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.000752 AC: 28 AN: 37246

South Asian (SAS) AF: 0.00334 AC: 268 AN: 80220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085138

Other (OTH) AF: 0.000632 AC: 37 AN: 58548

GnomAD4 genome AF: 0.000467 AC: 71 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.000766 AC XY: 57 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41502

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5170

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jun 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Fibrochondrogenesis 2 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Connective tissue disorder Uncertain:1

Jul 04, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4751-9A>G in intron 63 of COL11A2: This variant is not expected to have clinic al significance because it has been identified in 0.3% (22/8166) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs555680585). -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL11A2-related disorder Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Stickler Syndrome, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.1
DANN	Benign	0.64
PhyloP100		-3.8
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.010
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

Other links and lift over

dbSNP: rs555680585; hg19: chr6-33132750;