NM_080680.3:c.1119+1G>C

Variant names:

• chr6-33184144-C-G
• rs367706373
• NM_080680.3:c.1119+1G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_080680.3(COL11A2):​c.1119+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000247 in 1,214,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: COL11A2 NM_080680.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.63
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.034542315 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-33184144-C-G is Pathogenic according to our data. Variant chr6-33184144-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228527.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.1119+1G>C		splice_donor_variant, intron_variant	Intron 8 of 65	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.1119+1G>C		splice_donor_variant, intron_variant	Intron 8 of 65	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.861+848G>C		intron_variant	Intron 6 of 63	5		ENSP00000363840.4
COL11A2	ENST00000682718.1	n.*224G>C		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000247 AC: 3 AN: 1214854 Hom.: 0 Cov.: 31 AF XY: 0.00000166 AC XY: 1 AN XY: 602054

African (AFR) AF: 0.00 AC: 0 AN: 26300

American (AMR) AF: 0.00 AC: 0 AN: 37290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16896

East Asian (EAS) AF: 0.00 AC: 0 AN: 16806

South Asian (SAS) AF: 0.0000360 AC: 3 AN: 83226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4474

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 953956

Other (OTH) AF: 0.00 AC: 0 AN: 44016

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COL11A2-related disorder Pathogenic:1

Sep 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL11A2 c.1119+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL11A2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not specified Uncertain:1

Feb 26, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The c.1119+1G>C variant in COL11A2 (NM_080680.2) has not been previously reported and was absen t from large population studies. This variant occurs in the invariant region of the 5' splice consensus sequence of intron 8 and is predicted to cause altered s plicing, which may result in a truncated or absent protein. Loss-of-function var iants in the COL11A2 gene cause autosomal recessive OSMED syndrome and in frame deletions due to exon skipping have been reported in autosomal dominant Stickler syndrome. However, other transcript isoforms (NM_080681 and NM_080679) of the C OL11A2 gene do not contain exon 8 of this transcript, and the variant lies in an intronic region that is distant from any splice sites in those isoforms. To dat e, variants affecting exon 8 of this transcript isoform (NM_080680.2) or unique to this isoform have not been reported in affected individuals. Therefore, altho ugh the variant is expected to alter splicing, the biological importance of this exon and the impact of the variant on normal protein function cannot be predict ed. In summary, while there is some suspicion for a pathogenic role, the clinica l significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0086	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		3.6
GERP RS		3.7
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.010		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: rs367706373; hg19: chr6-33151921;