12-47997633-G-T

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.504C>A(p.Gly168=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 1,613,434 control chromosomes in the GnomAD database, including 39,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G168G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3371 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35736 hom.)
• Consequence: COL2A1 NM_001844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.78

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-47997633-G-T is Benign according to our data. Variant chr12-47997633-G-T is described in ClinVar as [Benign]. Clinvar id is 198471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47997633-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.504C>A	p.Gly168=	synonymous_variant	7/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.504C>A	p.Gly168=	synonymous_variant	7/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.297C>A	p.Gly99=	synonymous_variant	6/53	1
COL2A1	ENST00000474996.6	n.742C>A		non_coding_transcript_exon_variant	8/8	3

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30920 AN: 151866 Hom.: 3367 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.206 AC: 51154 AN: 248144 Hom.: 5583 AF XY: 0.208 AC XY: 28044 AN XY: 134594

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.329

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.218 AC: 318665 AN: 1461450 Hom.: 35736 Cov.: 34 AF XY: 0.217 AC XY: 158027 AN XY: 727034

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.204 AC: 30941 AN: 151984 Hom.: 3371 Cov.: 32 AF XY: 0.200 AC XY: 14891 AN XY: 74280

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.327

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.224

Alfa AF: 0.210 Hom.: 1496

Bravo AF: 0.206

Asia WGS AF: 0.232 AC: 806 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.238

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	-0.59
Cadd	Benign	2.0
Dann	Benign	0.64

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: rs3737548; hg19: chr12-48391416; COSMIC: COSV61528907; COSMIC: COSV61528907;