GeneBe

rs1555166658

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_001844.5(COL2A1):​c.2049+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

COL2A1
NM_001844.5 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.03

Publications

0 publications found
Variant links:
Genes affected
COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]
COL2A1 Gene-Disease associations (from GenCC):
  • achondrogenesis type II
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
  • Kniest dysplasia
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
  • platyspondylic dysplasia, Torrance type
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • spondyloepimetaphyseal dysplasia, Strudwick type
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • spondyloepiphyseal dysplasia congenita
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
  • spondyloepiphyseal dysplasia with metatarsal shortening
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • spondylometaphyseal dysplasia
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • spondyloperipheral dysplasia
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Stickler syndrome type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Illumina, Orphanet, Genomics England PanelApp
  • Stickler syndrome, type I, nonsyndromic ocular
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • avascular necrosis of femoral head, primary, 1
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Legg-Calve-Perthes disease
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
  • otospondylomegaepiphyseal dysplasia, autosomal recessive
    Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
  • spondyloepiphyseal dysplasia, Stanescu type
    Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • autosomal dominant rhegmatogenous retinal detachment
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • dysspondyloenchondromatosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial avascular necrosis of femoral head
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hypochondrogenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • multiple epiphyseal dysplasia, Beighton type
    Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • spondylometaphyseal dysplasia, Schmidt type
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • otospondylomegaepiphyseal dysplasia
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
  • vitreoretinopathy with phalangeal epiphyseal dysplasia
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012096774 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of -8, new splice context is: cagGTgacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-47983384-C-A is Pathogenic according to our data. Variant chr12-47983384-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2764709.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL2A1NM_001844.5 linkc.2049+1G>T splice_donor_variant, intron_variant Intron 31 of 53 ENST00000380518.8 NP_001835.3 P02458-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL2A1ENST00000380518.8 linkc.2049+1G>T splice_donor_variant, intron_variant Intron 31 of 53 1 NM_001844.5 ENSP00000369889.3 P02458-2
COL2A1ENST00000337299.7 linkc.1842+1G>T splice_donor_variant, intron_variant Intron 30 of 52 1 ENSP00000338213.6 P02458-1
COL2A1ENST00000483376.1 linkn.227+1G>T splice_donor_variant, intron_variant Intron 2 of 7 5
COL2A1ENST00000493991.5 linkn.973+1G>T splice_donor_variant, intron_variant Intron 14 of 36 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Sep 30, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change affects a donor splice site in intron 31 of the COL2A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with Stickler syndrome (PMID: 26626311). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.68
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
5.0
GERP RS
4.9
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.67
Position offset: 2
DS_DL_spliceai
0.99
Position offset: 1

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

Publications

Other links and lift over

dbSNP: rs1555166658; hg19: chr12-48377167; API