rs1554224412

Positions:

• chr6-33185763-AGAGAGA-ACGAGCCCAAT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_080680.3(COL11A2):​c.808_813delinsATTGGGCTCG​(p.Ser270IlefsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 26)
• Consequence: COL11A2 NM_080680.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.808_813delinsATTGGGCTCG	p.Ser270IlefsTer6	frameshift_variant	6/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.808_813delinsATTGGGCTCG	p.Ser270IlefsTer6	frameshift_variant	6/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.799-715_799-710delinsATTGGGCTCG		intron_variant		5		A1
COL11A2	ENST00000682718.1	n.625_630delinsATTGGGCTCG		non_coding_transcript_exon_variant	5/6

Frequencies

GnomAD3 genomes Cov.: 26

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 31, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser270fs variant in COL11A2 has not been previously reported in individuals with hearing loss, Stickler syndrome, or otospondylomegaepiphyseal dysplasia (OSMED). This va riant was absent from large population studies, though the ability of these stud ies to accurately detect indels may be limited. This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 270 and leads to a premature termination codon 6 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Loss of function of the COL11A2 gene has been primarily associated with autosomal rec essive OSMED. However, this variant occurs in an alternately spliced exon in COL 11A2, and no disease-causing loss-of-function variants have been previously repo rted in this region. This may suggest that the exon is not essential to protein function or that this variant may not have an impact on the protein product due to alternate splicing. Therefore the impact, if any, of this variant upon the pr otein is uncertain. In summary, while there is some suspicion for a pathogenic r ole, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554224412; hg19: chr6-33153541;