rs145960317

Variant names:

• chr6-33189092-C-G
• NM_080680.3:c.329G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-33189092-C-G
• chr6-33189092-C-T

Variant summary

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

The NM_080680.3(COL11A2):​c.329G>C​(p.Arg110Pro) variant causes a missense 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.27

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.329G>C	p.Arg110Pro	missense_variant	Exon 3 of 66	ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.329G>C	p.Arg110Pro	missense_variant	Exon 3 of 66	5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000395194.1	c.329G>C	p.Arg110Pro	missense_variant	Exon 3 of 5	1		ENSP00000378620.1
COL11A2	ENST00000374708.8	c.329G>C	p.Arg110Pro	missense_variant	Exon 3 of 64	5		ENSP00000363840.4
COL11A2	ENST00000682718.1	n.146G>C		non_coding_transcript_exon_variant	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Otospondylomegaepiphyseal dysplasia, autosomal dominant Uncertain:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 110 of the COL11A2 protein (p.Arg110Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL11A2-related conditions. 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 not expected to disrupt COL11A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.079	T;T;.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.58	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	.;.;.;.;L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N;N;N;D;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;T;D
Vest4		0.34
MutPred		0.59		Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);
MVP		0.53
MPC		1.1
ClinPred		0.84	D
GERP RS		-0.97
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33156869;