6-33174143-G-C

Variant names:

• chr6-33174143-G-C
• rs2744512
• NM_080680.3:c.2484+22C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080680.3(COL11A2):​c.2484+22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,597,208 control chromosomes in the GnomAD database, including 445,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47111 hom., cov: 29)
  • Exomes 𝑓: 0.74 (398397 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0620
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-33174143-G-C is Benign according to our data. Variant chr6-33174143-G-C is described in ClinVar as Benign. ClinVar VariationId is 262309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.2484+22C>G		intron_variant	Intron 32 of 65	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.2484+22C>G		intron_variant	Intron 32 of 65	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.2226+22C>G		intron_variant	Intron 30 of 63	5		ENSP00000363840.4
COL11A2	ENST00000361917.6	c.1056+22C>G		intron_variant	Intron 19 of 23	5		ENSP00000355123.2
COL11A2	ENST00000477772.1	n.272+2866C>G		intron_variant	Intron 5 of 8	2

Frequencies

GnomAD3 genomes AF: 0.784 AC: 118804 AN: 151600 Hom.: 47067 Cov.: 29

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.799

GnomAD2 exomes AF: 0.778 AC: 171874 AN: 220918 AF XY: 0.780

Gnomad AFR exome AF: 0.875

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.974

Gnomad FIN exome AF: 0.693

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.739 AC: 1068806 AN: 1445490 Hom.: 398397 Cov.: 50 AF XY: 0.744 AC XY: 533925 AN XY: 717806

African (AFR) AF: 0.883 AC: 29098 AN: 32936

American (AMR) AF: 0.800 AC: 34669 AN: 43362

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 20890 AN: 25778

East Asian (EAS) AF: 0.982 AC: 37946 AN: 38626

South Asian (SAS) AF: 0.888 AC: 74689 AN: 84066

European-Finnish (FIN) AF: 0.700 AC: 35926 AN: 51324

Middle Eastern (MID) AF: 0.831 AC: 4770 AN: 5742

European-Non Finnish (NFE) AF: 0.711 AC: 785334 AN: 1103898

Other (OTH) AF: 0.761 AC: 45484 AN: 59758

GnomAD4 genome AF: 0.784 AC: 118903 AN: 151718 Hom.: 47111 Cov.: 29 AF XY: 0.785 AC XY: 58152 AN XY: 74088

African (AFR) AF: 0.873 AC: 36097 AN: 41364

American (AMR) AF: 0.788 AC: 12040 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2781 AN: 3472

East Asian (EAS) AF: 0.972 AC: 4971 AN: 5114

South Asian (SAS) AF: 0.905 AC: 4360 AN: 4820

European-Finnish (FIN) AF: 0.708 AC: 7439 AN: 10506

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48719 AN: 67856

Other (OTH) AF: 0.801 AC: 1689 AN: 2108

Alfa AF: 0.717 Hom.: 4771

Bravo AF: 0.794

Asia WGS AF: 0.900 AC: 3131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 53 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 dominant nonsyndromic hearing loss 13 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibrochondrogenesis 2 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: 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	-0.92
CADD	Benign	2.6
DANN	Benign	0.27
PhyloP100		-0.062
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2744512; hg19: chr6-33141920;