12-47974193-C-T

Position:

chr12-47974193-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_001844.5(COL2A1):c.4213G>A(p.Gly1405Ser) variant causes a missense change. The variant allele was found at a frequency of 0.117 in 1,614,130 control chromosomes in the GnomAD database, including 16,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1477 hom., cov: 32)

Exomes 𝑓: 0.12 ( 14693 hom. )

Consequence

COL2A1
NM_001844.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.16

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:

COL2A1 (HGNC:):

COL2A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a domain Fibrillar collagen NC1 (size 234) in uniprot entity CO2A1_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) in NM_001844.5

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). GenCC has associacion of 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=0.0032954514).

BP6

Variant 12-47974193-C-T is Benign according to our data. Variant chr12-47974193-C-T is described in ClinVar as [Benign]. Clinvar id is 258238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47974193-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5 linkuse as main transcript	c.4213G>A	p.Gly1405Ser	missense_variant	53/54	ENST00000380518.8	NP_001835.3	P02458-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL2A1	ENST00000380518.8 linkuse as main transcript	c.4213G>A	p.Gly1405Ser	missense_variant	53/54	1	NM_001844.5	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7 linkuse as main transcript	c.4006G>A	p.Gly1336Ser	missense_variant	52/53	1		ENSP00000338213.6	P02458-1
COL2A1	ENST00000493991.5 linkuse as main transcript	n.3299G>A		non_coding_transcript_exon_variant	36/37	2

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16073

AN:

152140

Hom.:

1468

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0241

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0958

Gnomad OTH

AF:

0.109

GnomAD3 exomes

AF:

0.164

AC:

41274

AN:

251462

Hom.:

5474

AF XY:

0.155

AC XY:

21113

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.392

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.390

Gnomad SAS exome

AF:

0.135

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.0979

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.118

AC:

173200

AN:

1461872

Hom.:

14693

Cov.:

AF XY:

0.118

AC XY:

86007

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0176

Gnomad4 AMR exome

AF:

0.372

Gnomad4 ASJ exome

AF:

0.105

Gnomad4 EAS exome

AF:

0.433

Gnomad4 SAS exome

AF:

0.140

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.0984

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.106

AC:

16086

AN:

152258

Hom.:

1477

Cov.:

AF XY:

0.112

AC XY:

8301

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0240

Gnomad4 AMR

AF:

0.240

Gnomad4 ASJ

AF:

0.113

Gnomad4 EAS

AF:

0.380

Gnomad4 SAS

AF:

0.136

Gnomad4 FIN

AF:

0.140

Gnomad4 NFE

AF:

0.0958

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.108

Hom.:

2960

Bravo

AF:

0.113

TwinsUK

AF:

0.0992

AC:

368

ALSPAC

AF:

0.101

AC:

390

ESP6500AA

AF:

0.0222

AC:

ESP6500EA

AF:

0.0942

AC:

810

ExAC

AF:

0.150

AC:

18209

Asia WGS

AF:

0.251

AC:

872

AN:

3478

EpiCase

AF:

0.0998

EpiControl

AF:

0.0937

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Apr 07, 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	Eurofins Ntd Llc (ga)	Jan 11, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.026

D;D

Polyphen

1.0

D;D

Vest4

0.26

MPC

0.31

ClinPred

0.012

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.78

gMVP

0.58

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