rs112469769

Positions:

chr12-47999998-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001844.5(COL2A1):c.213C>T(p.Asp71Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 1,614,150 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 77 hom. )

Consequence

COL2A1
NM_001844.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.98

Variant links:

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]

COL2A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 12-47999998-G-A is Benign according to our data. Variant chr12-47999998-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 195149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47999998-G-A is described in Lovd as [Benign]. Variant chr12-47999998-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.98 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00707 (1077/152312) while in subpopulation NFE AF= 0.0108 (733/68024). AF 95% confidence interval is 0.0101. There are 8 homozygotes in gnomad4. There are 513 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1077 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5 link	c.213C>T	p.Asp71Asp	synonymous_variant	2/54	ENST00000380518.8	NP_001835.3	P02458-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL2A1	ENST00000380518.8 link	c.213C>T	p.Asp71Asp	synonymous_variant	2/54	1	NM_001844.5	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7 link	c.86-1567C>T		intron_variant		1		ENSP00000338213.6	P02458-1
COL2A1	ENST00000474996.6 link	n.451C>T		non_coding_transcript_exon_variant	3/8	3
COL2A1	ENST00000490609.2 link	n.446C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00708

AC:

1077

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00622

AC:

1551

AN:

249550

Hom.:

AF XY:

0.00634

AC XY:

858

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00187

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.00900

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.00817

AC:

11947

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

5854

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00197

Gnomad4 FIN exome

AF:

0.0152

Gnomad4 NFE exome

AF:

0.00937

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.00707

AC:

1077

AN:

152312

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

513

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0184

Gnomad4 NFE

AF:

0.0108

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00849

Hom.:

Bravo

AF:

0.00536

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00851

EpiControl

AF:

0.00628

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL2A1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:5

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	Feb 06, 2017	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	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Likely 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	-	- -

Stickler syndrome type 1

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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. -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

7.7

DANN

Benign

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over