GeneBe

rs1555166218

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001844.5(COL2A1):​c.2381delC​(p.Pro794LeufsTer87) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P794P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

COL2A1
NM_001844.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.89

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: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-47981803-AG-A is Pathogenic according to our data. Variant chr12-47981803-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 547258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL2A1NM_001844.5 linkc.2381delC p.Pro794LeufsTer87 frameshift_variant Exon 36 of 54 ENST00000380518.8 NP_001835.3 P02458-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL2A1ENST00000380518.8 linkc.2381delC p.Pro794LeufsTer87 frameshift_variant Exon 36 of 54 1 NM_001844.5 ENSP00000369889.3 P02458-2
COL2A1ENST00000337299.7 linkc.2174delC p.Pro725LeufsTer87 frameshift_variant Exon 35 of 53 1 ENSP00000338213.6 P02458-1
COL2A1ENST00000483376.1 linkn.559delC non_coding_transcript_exon_variant Exon 7 of 8 5
COL2A1ENST00000493991.5 linkn.1467delC non_coding_transcript_exon_variant Exon 19 of 37 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
160966
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1402270
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
692042
African (AFR)
AF:
0.00
AC:
0
AN:
31692
American (AMR)
AF:
0.00
AC:
0
AN:
36072
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25210
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35884
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79510
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5662
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1080658
Other (OTH)
AF:
0.00
AC:
0
AN:
58166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Jun 10, 2022
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant but additional evidence is not available (ClinVar Variant ID# 547258; ClinVar); This variant is associated with the following publications: (PMID: 10486316, 33726816) -

Sep 06, 2017
Clinical Genetics and Genomics, Karolinska University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Pro794Leufs*87) in the COL2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Stickler syndrome (PMID: 10486316). This variant is also known as deletion of nt 22,620 (C) in E34. ClinVar contains an entry for this variant (Variation ID: 547258). For these reasons, this variant has been classified as Pathogenic. -

Stickler syndrome type 1 Pathogenic:2
Jan 03, 2022
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000547258, PMID:10486316). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
9.9
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1555166218; hg19: chr12-48375586; COSMIC: COSV61528753; COSMIC: COSV61528753; API