chr6-33177216-C-T

Position:

• chr6-33177216-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PP2 PP3_Strong PP5_Moderate

The NM_080680.3(COL11A2):​c.1981G>A​(p.Gly661Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.42

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_080680.3 (COL11A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL11A2. . Gene score misZ 2.3685 (greater than the threshold 3.09). Trascript score misZ 3.3886 (greater than threshold 3.09). GenCC has associacion of gene with otospondylomegaepiphyseal dysplasia, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss, autosomal recessive nonsyndromic hearing loss 53, otospondylomegaepiphyseal dysplasia, autosomal dominant, nonsyndromic genetic hearing loss, fibrochondrogenesis, hearing loss, autosomal recessive, otospondylomegaepiphyseal dysplasia, autosomal recessive.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 6-33177216-C-T is Pathogenic according to our data. Variant chr6-33177216-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17121.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-33177216-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.1981G>A	p.Gly661Arg	missense_variant	24/66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.1981G>A	p.Gly661Arg	missense_variant	24/66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.1723G>A	p.Gly575Arg	missense_variant	22/64	5		ENSP00000363840.4
COL11A2	ENST00000361917.6	c.553G>A	p.Gly185Arg	missense_variant	11/24	5		ENSP00000355123.2
COL11A2	ENST00000477772.1	n.200G>A		non_coding_transcript_exon_variant	4/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000813 AC: 2 AN: 245900 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460744 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 726692

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000993 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Otospondylomegaepiphyseal dysplasia, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 13, 1997

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 29, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 661 of the COL11A2 protein (p.Gly661Arg). This variant is present in population databases (rs121912945, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive otospondylomegaepiphyseal dysplasia (PMID: 7859284). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly175Arg. ClinVar contains an entry for this variant (Variation ID: 17121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL11A2 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.098	T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.90
MutPred		1.0		.;Loss of relative solvent accessibility (P = 0.0676);.;
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		4.2
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912945; hg19: chr6-33144993;