6-33172061-G-C

Variant names:

• chr6-33172061-G-C
• rs997533180
• NM_080680.3:c.3031C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080680.3(COL11A2):​c.3031C>G​(p.Pro1011Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1011R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 41 of 66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 41 of 66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.2773C>G	p.Pro925Ala	missense_variant	Exon 39 of 64	5		ENSP00000363840.4
COL11A2	ENST00000477772.1	n.272+4948C>G		intron_variant	Intron 5 of 8	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460760 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro1011Ala variant in COL11A2 has not been previously reported in individu als with hearing loss or Stickler Syndrome and was absent from large population studies. Computational prediction tools and conservation analysis suggest that t his variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, the clinical significance of the p. Pro1011Ala variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.10	T;T;T
Vest4		0.40
MutPred		0.33		.;Loss of glycosylation at P1011 (P = 0.0134);.;
MVP		0.89
MPC		0.85
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 42

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

Publications

LitVar

Other links and lift over

dbSNP: rs997533180; hg19: chr6-33139838;