chr6-33178195-C-T

Variant names:

• chr6-33178195-C-T
• rs3129202
• NM_080680.3:c.1819-10G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_080680.3(COL11A2):​c.1819-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,611,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (0 hom.)
• Consequence: COL11A2 NM_080680.3 intron
• Scores: Splicing: ADA: 0.0001288
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.718
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-33178195-C-T is Benign according to our data. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532. Variant chr6-33178195-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226532.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00025 (38/152070) while in subpopulation NFE AF = 0.000397 (27/67928). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.1819-10G>A		intron_variant	Intron 20 of 65	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.1819-10G>A		intron_variant	Intron 20 of 65	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.1561-10G>A		intron_variant	Intron 18 of 63	5		ENSP00000363840.4
COL11A2	ENST00000361917.6	c.444+113G>A		intron_variant	Intron 8 of 23	5		ENSP00000355123.2

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000342 AC: 84 AN: 245908 AF XY: 0.000395

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000417 AC: 608 AN: 1459238 Hom.: 0 Cov.: 34 AF XY: 0.000420 AC XY: 305 AN XY: 725776

African (AFR) AF: 0.000149 AC: 5 AN: 33460

American (AMR) AF: 0.0000672 AC: 3 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26052

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86150

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.000460 AC: 511 AN: 1110898

Other (OTH) AF: 0.000514 AC: 31 AN: 60312

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41490

American (AMR) AF: 0.000327 AC: 5 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1819-10G>A in Intron 20 of COL11A2: This variant is not expected to have clinica l significance because it has been identified in 9.0% (7/78) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; r s3129202). -

Sep 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL11A2 c.1819-10G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 245908 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1819-10G>A in individuals affected with COL11A2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 25, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant 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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.072
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: rs3129202; hg19: chr6-33145972;