rs34392760

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001844.5(COL2A1):c.426A>T(p.Glu142Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 1,614,054 control chromosomes in the GnomAD database, including 2,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 149 hom., cov: 33)

Exomes 𝑓: 0.048 ( 1878 hom. )

Consequence

COL2A1
NM_001844.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.249

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, COL2A1

BP4

Computational evidence support a benign effect (MetaRNN=0.0039563477).

BP6

Variant 12-47997874-T-A is Benign according to our data. Variant chr12-47997874-T-A is described in ClinVar as [Benign]. Clinvar id is 258239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47997874-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5 linkuse as main transcript	c.426A>T	p.Glu142Asp	missense_variant	6/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8 linkuse as main transcript	c.426A>T	p.Glu142Asp	missense_variant	6/54	1	NM_001844.5	P1	P02458-2
COL2A1	ENST00000337299.7 linkuse as main transcript	c.219A>T	p.Glu73Asp	missense_variant	5/53	1			P02458-1
COL2A1	ENST00000474996.6 linkuse as main transcript	n.664A>T		non_coding_transcript_exon_variant	7/8	3

Frequencies

GnomAD3 genomes

AF:

0.0366

AC:

5565

AN:

152206

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00917

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.0752

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0232

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0421

GnomAD3 exomes

AF:

0.0376

AC:

9443

AN:

251170

Hom.:

246

AF XY:

0.0378

AC XY:

5137

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00819

Gnomad AMR exome

AF:

0.0268

Gnomad ASJ exome

AF:

0.0695

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.0562

Gnomad OTH exome

AF:

0.0463

GnomAD4 exome

AF:

0.0481

AC:

70318

AN:

1461730

Hom.:

1878

Cov.:

AF XY:

0.0473

AC XY:

34426

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00824

Gnomad4 AMR exome

AF:

0.0280

Gnomad4 ASJ exome

AF:

0.0711

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0132

Gnomad4 FIN exome

AF:

0.0289

Gnomad4 NFE exome

AF:

0.0550

Gnomad4 OTH exome

AF:

0.0451

GnomAD4 genome

AF:

0.0365

AC:

5563

AN:

152324

Hom.:

149

Cov.:

AF XY:

0.0339

AC XY:

2525

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00914

Gnomad4 AMR

AF:

0.0409

Gnomad4 ASJ

AF:

0.0752

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.0232

Gnomad4 NFE

AF:

0.0568

Gnomad4 OTH

AF:

0.0412

Alfa

AF:

0.0520

Hom.:

Bravo

AF:

0.0359

TwinsUK

AF:

0.0502

AC:

186

ALSPAC

AF:

0.0623

AC:

240

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0530

AC:

456

ExAC

AF:

0.0381

AC:

4622

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0569

EpiControl

AF:

0.0616

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

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. -

Type II Collagenopathies

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Benign

0.93

DEOGEN2

Uncertain

0.42

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

-0.025

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.52

N;N

REVEL

Benign

0.29

Sift

Benign

0.49

T;T

Sift4G

Benign

0.72

T;T

Polyphen

0.0020

B;B

Vest4

0.061

MutPred

0.16

Loss of methylation at K140 (P = 0.1224);.;

MPC

0.11

ClinPred

0.0062

GERP RS

3.9

Varity_R

0.15

gMVP

0.20

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