rs3803183

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5PP2BP4_StrongBP6_Very_StrongBA1

The NM_001844.5(COL2A1):c.25A>T(p.Thr9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,549,070 control chromosomes in the GnomAD database, including 511,699 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.76 ( 44143 hom., cov: 32)

Exomes 𝑓: 0.81 ( 467556 hom. )

Consequence

COL2A1
NM_001844.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.94

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 -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-48004296-G-T is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL2A1. . Gene score misZ: 3.2926 (greater than the threshold 3.09). Trascript score misZ: 5.3726 (greater than threshold 3.09). The gene has 376 curated pathogenic missense variants (we use a threshold of 10). The gene has 125 curated benign missense variants. GenCC has associacion of the gene with spondylometaphyseal dysplasia, Schmidt type, spondyloepiphyseal dysplasia congenita, hypochondrogenesis, autosomal dominant rhegmatogenous retinal detachment, spondyloperipheral dysplasia, Kniest dysplasia, familial avascular necrosis of femoral head, spondylometaphyseal dysplasia, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, otospondylomegaepiphyseal dysplasia, autosomal recessive, multiple epiphyseal dysplasia, Beighton type, otospondylomegaepiphyseal dysplasia, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia, Stanescu type, platyspondylic dysplasia, Torrance type, Stickler syndrome type 1, dysspondyloenchondromatosis, vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, avascular necrosis of femoral head, primary, 1, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloepimetaphyseal dysplasia, Strudwick type.

BP4

Computational evidence support a benign effect (MetaRNN=6.506543E-6).

BP6

Variant 12-48004297-T-A is Benign according to our data. Variant chr12-48004297-T-A is described in ClinVar as [Benign]. Clinvar id is 93788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48004297-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5 link	c.25A>T	p.Thr9Ser	missense_variant	1/54	ENST00000380518.8	NP_001835.3	P02458-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8 link	c.25A>T	p.Thr9Ser	missense_variant	1/54	1	NM_001844.5	ENSP00000369889.3		P02458-2

Frequencies

GnomAD3 genomes

AF:

0.757

AC:

114999

AN:

151936

Hom.:

44122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.668

Gnomad AMI

AF:

0.757

Gnomad AMR

AF:

0.675

Gnomad ASJ

AF:

0.803

Gnomad EAS

AF:

0.597

Gnomad SAS

AF:

0.748

Gnomad FIN

AF:

0.756

Gnomad MID

AF:

0.848

Gnomad NFE

AF:

0.839

Gnomad OTH

AF:

0.767

GnomAD3 exomes

AF:

0.742

AC:

113435

AN:

152974

Hom.:

43153

AF XY:

0.753

AC XY:

60866

AN XY:

80800

show subpopulations

Gnomad AFR exome

AF:

0.666

Gnomad AMR exome

AF:

0.554

Gnomad ASJ exome

AF:

0.790

Gnomad EAS exome

AF:

0.600

Gnomad SAS exome

AF:

0.766

Gnomad FIN exome

AF:

0.748

Gnomad NFE exome

AF:

0.840

Gnomad OTH exome

AF:

0.777

GnomAD4 exome

AF:

0.815

AC:

1138155

AN:

1397016

Hom.:

467556

Cov.:

AF XY:

0.814

AC XY:

561221

AN XY:

689082

show subpopulations

Gnomad4 AFR exome

AF:

0.653

Gnomad4 AMR exome

AF:

0.573

Gnomad4 ASJ exome

AF:

0.795

Gnomad4 EAS exome

AF:

0.570

Gnomad4 SAS exome

AF:

0.765

Gnomad4 FIN exome

AF:

0.757

Gnomad4 NFE exome

AF:

0.843

Gnomad4 OTH exome

AF:

0.796

GnomAD4 genome

AF:

0.757

AC:

115070

AN:

152054

Hom.:

44143

Cov.:

AF XY:

0.750

AC XY:

55765

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.668

Gnomad4 AMR

AF:

0.674

Gnomad4 ASJ

AF:

0.803

Gnomad4 EAS

AF:

0.596

Gnomad4 SAS

AF:

0.749

Gnomad4 FIN

AF:

0.756

Gnomad4 NFE

AF:

0.839

Gnomad4 OTH

AF:

0.764

Alfa

AF:

0.816

Hom.:

38303

Bravo

AF:

0.743

TwinsUK

AF:

0.839

AC:

3111

ALSPAC

AF:

0.843

AC:

3250

ESP6500AA

AF:

0.688

AC:

2615

ESP6500EA

AF:

0.843

AC:

6023

ExAC

AF:

0.633

AC:

23641

Asia WGS

AF:

0.654

AC:

2277

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 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)	Jul 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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 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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.37

T;T

MetaRNN

Benign

0.0000065

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.34

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.21

Sift

Benign

0.65

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0

B;B

Vest4

0.079

MPC

0.11

ClinPred

0.0058

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.65

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