rs17122498

chr12-47974681-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001844.5(COL2A1):c.4068C>T(p.Gly1356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,106 control chromosomes in the GnomAD database, including 1,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (422 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (643 hom.)
• Consequence: COL2A1 NM_001844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.278

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-47974681-G-A is Benign according to our data. Variant chr12-47974681-G-A is described in ClinVar as [Benign]. Clinvar id is 258235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47974681-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.4068C>T	p.Gly1356=	synonymous_variant	52/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.4068C>T	p.Gly1356=	synonymous_variant	52/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.3861C>T	p.Gly1287=	synonymous_variant	51/53	1
COL2A1	ENST00000493991.5	n.3154C>T		non_coding_transcript_exon_variant	35/37	2

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6516 AN: 152146 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0202 AC: 5087 AN: 251476 Hom.: 270 AF XY: 0.0198 AC XY: 2686 AN XY: 135916

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00707

Gnomad SAS exome AF: 0.0692

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00879 AC: 12854 AN: 1461842 Hom.: 643 Cov.: 32 AF XY: 0.00998 AC XY: 7257 AN XY: 727222

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00368

Gnomad4 SAS exome AF: 0.0658

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000666

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0430 AC: 6542 AN: 152264 Hom.: 422 Cov.: 32 AF XY: 0.0428 AC XY: 3185 AN XY: 74448

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00656

Gnomad4 SAS AF: 0.0794

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0119 Hom.: 123

Bravo AF: 0.0467

Asia WGS AF: 0.0750 AC: 262 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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	-0.38
Cadd	Benign	11
Dann	Benign	0.69

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: rs17122498; hg19: chr12-48368464;