12-47974758-C-T

Variant names:

Variant summary

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

The NM_001844.5(COL2A1):c.3991G>A(p.Val1331Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,614,076 control chromosomes in the GnomAD database, including 4,355 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 0.052 ( 288 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4067 hom. )

Consequence

COL2A1
NM_001844.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.08

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.

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 the COL2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 376 curated pathogenic missense variants (we use a threshold of 10). The gene has 125 curated benign missense variants. Gene score misZ: 3.2926 (above the threshold of 3.09). Trascript score misZ: 5.3726 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.0019786358).

BP6

Variant 12-47974758-C-T is Benign according to our data. Variant chr12-47974758-C-T is described in ClinVar as [Benign]. Clinvar id is 258234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47974758-C-T is described in Lovd as [Benign]. Variant chr12-47974758-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5 link	c.3991G>A	p.Val1331Ile	missense_variant	Exon 52 of 54	ENST00000380518.8	NP_001835.3	P02458-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL2A1	ENST00000380518.8 link	c.3991G>A	p.Val1331Ile	missense_variant	Exon 52 of 54	1	NM_001844.5	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7 link	c.3784G>A	p.Val1262Ile	missense_variant	Exon 51 of 53	1		ENSP00000338213.6	P02458-1
COL2A1	ENST00000493991.5 link	n.3077G>A		non_coding_transcript_exon_variant	Exon 35 of 37	2

Frequencies

GnomAD3 genomes

AF:

0.0524

AC:

7968

AN:

152114

Hom.:

289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.0166

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0792

Gnomad OTH

AF:

0.0435

GnomAD3 exomes

AF:

0.0535

AC:

13459

AN:

251492

Hom.:

486

AF XY:

0.0537

AC XY:

7303

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0165

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.0167

Gnomad SAS exome

AF:

0.0223

Gnomad FIN exome

AF:

0.0904

Gnomad NFE exome

AF:

0.0777

Gnomad OTH exome

AF:

0.0559

GnomAD4 exome

AF:

0.0702

AC:

102563

AN:

1461844

Hom.:

4067

Cov.:

AF XY:

0.0689

AC XY:

50122

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0154

Gnomad4 AMR exome

AF:

0.0259

Gnomad4 ASJ exome

AF:

0.0215

Gnomad4 EAS exome

AF:

0.0203

Gnomad4 SAS exome

AF:

0.0218

Gnomad4 FIN exome

AF:

0.0904

Gnomad4 NFE exome

AF:

0.0802

Gnomad4 OTH exome

AF:

0.0585

GnomAD4 genome

AF:

0.0523

AC:

7963

AN:

152232

Hom.:

288

Cov.:

AF XY:

0.0523

AC XY:

3893

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0188

Gnomad4 AMR

AF:

0.0300

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.0164

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.0924

Gnomad4 NFE

AF:

0.0792

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0643

Hom.:

847

Bravo

AF:

0.0456

TwinsUK

AF:

0.0796

AC:

295

ALSPAC

AF:

0.0874

AC:

337

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.0707

AC:

608

ExAC

AF:

0.0549

AC:

6665

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0664

EpiControl

AF:

0.0696

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Stickler syndrome type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.11

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

0.91

T;T

Polyphen

0.0010

B;B

Vest4

0.043

MPC

0.26

ClinPred

0.0088

GERP RS

4.9

Varity_R

0.048

gMVP

0.34

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