rs41317939

Positions:

• chr12-47984597-A-G

Variant summary

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

The ENST00000380518.8(COL2A1):​c.1836T>C​(p.Gly612=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,613,810 control chromosomes in the GnomAD database, including 3,806 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (246 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3560 hom.)
• Consequence: COL2A1 ENST00000380518.8 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.04

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=-0.77).
• BP6: Variant 12-47984597-A-G is Benign according to our data. Variant chr12-47984597-A-G is described in ClinVar as [Benign]. Clinvar id is 258217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47984597-A-G is described in Lovd as [Benign]. Variant chr12-47984597-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.1836T>C	p.Gly612=	splice_region_variant, synonymous_variant	28/54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.1836T>C	p.Gly612=	splice_region_variant, synonymous_variant	28/54	1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.1629T>C	p.Gly543=	splice_region_variant, synonymous_variant	27/53	1		ENSP00000338213
COL2A1	ENST00000493991.5	n.760T>C		splice_region_variant, non_coding_transcript_exon_variant	11/37	2

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7504 AN: 152192 Hom.: 246 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0862

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0745

Gnomad OTH AF: 0.0444

GnomAD3 exomes AF: 0.0477 AC: 11965 AN: 250704 Hom.: 437 AF XY: 0.0474 AC XY: 6424 AN XY: 135614

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0873

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0646 AC: 94408 AN: 1461500 Hom.: 3560 Cov.: 33 AF XY: 0.0630 AC XY: 45834 AN XY: 727066

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0874

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.0550

GnomAD4 genome AF: 0.0493 AC: 7509 AN: 152310 Hom.: 246 Cov.: 33 AF XY: 0.0490 AC XY: 3646 AN XY: 74482

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.0289

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0862

Gnomad4 NFE AF: 0.0744

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0599 Hom.: 173

Bravo AF: 0.0422

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0633

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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 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	-0.77
CADD	Benign	0.021
DANN	Benign	0.57

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: rs41317939; hg19: chr12-48378380; COSMIC: COSV61530805; COSMIC: COSV61530805;