rs1034762

Positions:

• chr12-47995860-A-C
• chr12-47995860-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000380518.8(COL2A1):​c.654+15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 1,611,240 control chromosomes in the GnomAD database, including 536,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47419 hom., cov: 31)
  • Exomes 𝑓: 0.81 (488983 hom.)
• Consequence: COL2A1 ENST00000380518.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.92

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-47995860-A-C is Benign according to our data. Variant chr12-47995860-A-C is described in ClinVar as [Benign]. Clinvar id is 258243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47995860-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.654+15T>G		intron_variant		ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.654+15T>G		intron_variant		1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.447+15T>G		intron_variant		1		ENSP00000338213

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119283 AN: 151958 Hom.: 47385 Cov.: 31

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.788

GnomAD3 exomes AF: 0.738 AC: 185608 AN: 251476 Hom.: 70918 AF XY: 0.745 AC XY: 101323 AN XY: 135918

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.791

Gnomad EAS exome AF: 0.509

Gnomad SAS exome AF: 0.668

Gnomad FIN exome AF: 0.759

Gnomad NFE exome AF: 0.846

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.813 AC: 1186578 AN: 1459164 Hom.: 488983 Cov.: 35 AF XY: 0.810 AC XY: 588402 AN XY: 726142

Gnomad4 AFR exome AF: 0.777

Gnomad4 AMR exome AF: 0.530

Gnomad4 ASJ exome AF: 0.797

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.766

Gnomad4 NFE exome AF: 0.852

Gnomad4 OTH exome AF: 0.797

GnomAD4 genome AF: 0.785 AC: 119368 AN: 152076 Hom.: 47419 Cov.: 31 AF XY: 0.774 AC XY: 57520 AN XY: 74328

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.660

Gnomad4 ASJ AF: 0.806

Gnomad4 EAS AF: 0.515

Gnomad4 SAS AF: 0.645

Gnomad4 FIN AF: 0.766

Gnomad4 NFE AF: 0.847

Gnomad4 OTH AF: 0.782

Alfa AF: 0.811 Hom.: 28768

Bravo AF: 0.775

Asia WGS AF: 0.593 AC: 2067 AN: 3478

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, 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	-	- -
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. -

not provided Benign:2

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

Stickler syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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	-0.84
CADD	Benign	1.2
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1034762; hg19: chr12-48389643; COSMIC: COSV61528903; COSMIC: COSV61528903;