rs886043410

Positions:

• chr12-47982109-G-A
• chr12-47982109-G-C

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.2353C>T​(p.Arg785*) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL2A1 NM_001844.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.8412
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.776

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]

LOC105369752 (HGNC:):

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 12-47982109-G-A is Pathogenic according to our data. Variant chr12-47982109-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 286497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47982109-G-A is described in Lovd as [Pathogenic]. Variant chr12-47982109-G-A is described in Lovd as [Pathogenic]. Variant chr12-47982109-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.2353C>T	p.Arg785*	stop_gained, splice_region_variant	35/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.2353C>T	p.Arg785*	stop_gained, splice_region_variant	35/54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.2146C>T	p.Arg716*	stop_gained, splice_region_variant	34/53	1		ENSP00000338213.6
COL2A1	ENST00000483376.1	n.531C>T		splice_region_variant, non_coding_transcript_exon_variant	6/8	5
COL2A1	ENST00000493991.5	n.1277C>T		non_coding_transcript_exon_variant	18/37	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Arg785*) 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 individuals with autosomal dominant Stickler syndrome (PMID: 10729292, 28559085). It has also been observed to segregate with disease in related individuals. This variant is also known as 22314 C-T, R585X. ClinVar contains an entry for this variant (Variation ID: 286497). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2022	Not observed at significant frequency in large population cohorts (gnomAD); 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; Reported in ClinVar (ClinVar Variant ID# 286497; ClinVar); This variant is associated with the following publications: (PMID: 25525159, 20513134, 10729292, 26443184, 23022073, 29453956, 20179744, 31758797, 32756486, 32639332, 27408751, 28559085, 26582918) -

Stickler syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Oct 20, 2023

- -

Stickler syndrome, type I, nonsyndromic ocular;C2020284:Stickler syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PS4_Moderate+PP1_Strong+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.97
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.020		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: rs886043410; hg19: chr12-48375892; COSMIC: COSV61531528; COSMIC: COSV61531528;