rs794727261

chr12-47999953-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001844.5(COL2A1):c.258C>A(p.Cys86Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL2A1 NM_001844.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.677

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 12-47999953-G-T is Pathogenic according to our data. Variant chr12-47999953-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 195148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47999953-G-T is described in Lovd as [Pathogenic]. Variant chr12-47999953-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.258C>A	p.Cys86Ter	stop_gained	2/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.258C>A	p.Cys86Ter	stop_gained	2/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.86-1522C>A		intron_variant		1
COL2A1	ENST00000474996.6	n.496C>A		non_coding_transcript_exon_variant	3/8	3
COL2A1	ENST00000490609.2	n.491C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change creates a premature translational stop signal (p.Cys86*) 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: 12429249, 23592912, 28559085). ClinVar contains an entry for this variant (Variation ID: 195148). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2021	Reported in patients with Stickler syndrome and described as being associated with a high incidence of ocular involvement and a lower incidence of the systemic features associated with Stickler syndrome (Donoso et al., 2002; Parma et al., 2002; Stone et al., 2017); Not observed in large population cohorts (Lek et al., 2016); Nonsense 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; Located in exon 2, which is an alternatively spliced exon; a genotype-phenotype correlation of variants in exon 2 with a predominantly ocular phenotype has been proposed due to differential tissue expression of alternative isoforms (Donoso et al., 2003; McAlinden et al., 2008); Reported in ClinVar as pathogenic (ClinVar Variant ID# 195148; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 12429249, 12429250, 27234559, 28559085, 32039712, 23592912, 17721977) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2017	- -

Legg-Calve-Perthes disease;C0220685:Achondrogenesis type II;C0265279:Kniest dysplasia;C0432214:Namaqualand hip dysplasia;C0796173:Spondyloperipheral dysplasia;C1835437:Platyspondylic dysplasia, Torrance type;C1836080:Stickler syndrome, type I, nonsyndromic ocular;C1836683:Spondyloepiphyseal dysplasia with metatarsal shortening;C1851536:Multiple epiphyseal dysplasia, Beighton type;C2020284:Stickler syndrome type 1;C2745959:Spondyloepiphyseal dysplasia congenita;C4225273:Spondyloepiphyseal dysplasia, Stanescu type;C4551562:Avascular necrosis of femoral head, primary, 1;C4759767:Spondylometaphyseal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;D
Vest4		0.91
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs794727261; hg19: chr12-48393736;