rs35765893

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_080680.3(COL11A2):​c.230C>T​(p.Pro77Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P77Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

COL11A2
NM_080680.3 missense, splice_region

Scores

3
8
7
Splicing: ADA: 0.9969
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.97
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL11A2NM_080680.3 linkuse as main transcriptc.230C>T p.Pro77Leu missense_variant, splice_region_variant 2/66 ENST00000341947.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL11A2ENST00000341947.7 linkuse as main transcriptc.230C>T p.Pro77Leu missense_variant, splice_region_variant 2/665 NM_080680.3 P4
COL11A2ENST00000395194.1 linkuse as main transcriptc.230C>T p.Pro77Leu missense_variant, splice_region_variant 2/51 P13942-9
COL11A2ENST00000374708.8 linkuse as main transcriptc.230C>T p.Pro77Leu missense_variant, splice_region_variant 2/645 A1
COL11A2ENST00000682718.1 linkuse as main transcriptn.47C>T splice_region_variant, non_coding_transcript_exon_variant 1/6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.036
T
BayesDel_noAF
Benign
-0.19
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T;T;.;T;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.97
D
M_CAP
Benign
0.034
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
.;.;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.1
D;D;D;D;D
REVEL
Benign
0.29
Sift
Uncertain
0.015
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Vest4
0.66
MutPred
0.62
Loss of disorder (P = 0.0358);Loss of disorder (P = 0.0358);Loss of disorder (P = 0.0358);Loss of disorder (P = 0.0358);Loss of disorder (P = 0.0358);
MVP
0.58
MPC
0.61
ClinPred
0.93
D
GERP RS
4.2
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35765893; hg19: chr6-33157099; API