rs2276454

Positions:

• chr12-47982508-G-A
• chr12-47982508-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001844.5(COL2A1):​c.2295C>T​(p.Gly765Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,609,760 control chromosomes in the GnomAD database, including 133,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11563 hom., cov: 33)
  • Exomes 𝑓: 0.40 (121588 hom.)
• Consequence: COL2A1 NM_001844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.142

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-47982508-G-A is Benign according to our data. Variant chr12-47982508-G-A is described in ClinVar as [Benign]. Clinvar id is 258225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47982508-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.142 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.2295C>T	p.Gly765Gly	synonymous_variant	34/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.2295C>T	p.Gly765Gly	synonymous_variant	34/54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.2088C>T	p.Gly696Gly	synonymous_variant	33/53	1		ENSP00000338213.6
COL2A1	ENST00000483376.1	n.473C>T		non_coding_transcript_exon_variant	5/8	5
COL2A1	ENST00000493991.5	n.1219C>T		non_coding_transcript_exon_variant	17/37	2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58356 AN: 151954 Hom.: 11564 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.405

GnomAD3 exomes AF: 0.390 AC: 96877 AN: 248278 Hom.: 20075 AF XY: 0.402 AC XY: 54026 AN XY: 134464

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.598

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.394

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.404 AC: 588640 AN: 1457688 Hom.: 121588 Cov.: 35 AF XY: 0.407 AC XY: 295367 AN XY: 725366

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.394

Gnomad4 EAS exome AF: 0.567

Gnomad4 SAS exome AF: 0.467

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.384 AC: 58368 AN: 152072 Hom.: 11563 Cov.: 33 AF XY: 0.381 AC XY: 28306 AN XY: 74332

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.401

Alfa AF: 0.398 Hom.: 23083

Bravo AF: 0.382

Asia WGS AF: 0.452 AC: 1571 AN: 3478

EpiCase AF: 0.421

EpiControl AF: 0.422

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Stickler syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Type II Collagenopathies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.8
DANN	Benign	0.65

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: rs2276454; hg19: chr12-48376291;