rs748459670

Positions:

• chr12-47978015-G-A
• chr12-47978015-G-C

Variant summary

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

The ENST00000380518.8(COL2A1):​c.3106C>T​(p.Arg1036Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL2A1 ENST00000380518.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.62

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 12-47978015-G-A is Pathogenic according to our data. Variant chr12-47978015-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 197503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47978015-G-A is described in Lovd as [Pathogenic]. Variant chr12-47978015-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.3106C>T	p.Arg1036Ter	stop_gained	44/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.3106C>T	p.Arg1036Ter	stop_gained	44/54	1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.2899C>T	p.Arg967Ter	stop_gained	43/53	1		ENSP00000338213
COL2A1	ENST00000493991.5	n.2192C>T		non_coding_transcript_exon_variant	27/37	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249916 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135382

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461076 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	This sequence change creates a premature translational stop signal (p.Arg1036*) 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 present in population databases (rs748459670, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Stickler syndrome type 1 (PMID: 16752401, 25809783). ClinVar contains an entry for this variant (Variation ID: 197503). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 27, 2023	The COL2A1 c.3106C>T; p.Arg1036Ter variant (rs748459670) is reported in the literature in individuals with Stickler syndrome (Choi 2021, Richards 2006, Savasta 2015). This variant is also reported in ClinVar (Variation ID: 197503). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Choi SI et al. Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1. Genes (Basel). 2021 Oct 5;12(10):1578. PMID: 34680973. Richards AJ et al. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. PMID: 16752401. Savasta S et al. Stickler syndrome associated with epilepsy: report of three cases. Eur J Pediatr. 2015 May;174(5):697-701. PMID: 25809783. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2023	Has been reported in multiple individuals with Stickler syndrome (Richards et al., 2006; Hoornaert et al., 2010; Richards et al., 2010; Savasta et al., 2015; Barat-Houari et al., 2016a; Kondo et al., 2016; Huang et al., 2020; Choi et al., 2021); 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; This variant is associated with the following publications: (PMID: 25809783, 25525159, 16752401, 20179744, 23891399, 29453956, 26443184, 27408751, 29661559, 20513134, 34680973, 32756486) -

Stickler syndrome type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PM6_Supporting+PS4+PP1_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs748459670; hg19: chr12-48371798; COSMIC: COSV61527621; COSMIC: COSV61527621;