rs1635553

chr12-47981785-A-G

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.2400T>C(p.Asn800=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 1,553,398 control chromosomes in the GnomAD database, including 173,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16240 hom., cov: 33)
  • Exomes 𝑓: 0.47 (157432 hom.)
• Consequence: COL2A1 NM_001844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.19

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]

LOC105369752 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-47981785-A-G is Benign according to our data. Variant chr12-47981785-A-G is described in ClinVar as [Benign]. Clinvar id is 93787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47981785-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.2400T>C	p.Asn800=	synonymous_variant	36/54	ENST00000380518.8
LOC105369752	XR_944910.2	n.218+359A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.2400T>C	p.Asn800=	synonymous_variant	36/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.2193T>C	p.Asn731=	synonymous_variant	35/53	1
COL2A1	ENST00000483376.1	n.578T>C		non_coding_transcript_exon_variant	7/8	5
COL2A1	ENST00000493991.5	n.1486T>C		non_coding_transcript_exon_variant	19/37	2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69776 AN: 152034 Hom.: 16235 Cov.: 33

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.464

GnomAD3 exomes AF: 0.442 AC: 70988 AN: 160560 Hom.: 16365 AF XY: 0.453 AC XY: 38308 AN XY: 84504

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.592

Gnomad SAS exome AF: 0.491

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.472 AC: 661051 AN: 1401246 Hom.: 157432 Cov.: 47 AF XY: 0.473 AC XY: 327200 AN XY: 691380

Gnomad4 AFR exome AF: 0.463

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.408

Gnomad4 EAS exome AF: 0.563

Gnomad4 SAS exome AF: 0.489

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.482

GnomAD4 genome AF: 0.459 AC: 69798 AN: 152152 Hom.: 16240 Cov.: 33 AF XY: 0.454 AC XY: 33742 AN XY: 74386

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.475

Gnomad4 OTH AF: 0.459

Alfa AF: 0.467 Hom.: 28621

Bravo AF: 0.455

Asia WGS AF: 0.473 AC: 1644 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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. -

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. -

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 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	-0.79
Cadd	Benign	0.027
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1635553; hg19: chr12-48375568; COSMIC: COSV61531476; COSMIC: COSV61531476;