Genetic Variant COL2A1:c.86-915C>A (chr12-48001040-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001844.5(COL2A1):c.86-915C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,214 control chromosomes in the GnomAD database, including 8,089 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8089 hom., cov: 33)

Exomes 𝑓: 0.22 ( 0 hom. )

Consequence

COL2A1
NM_001844.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.46

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

achondrogenesis type II
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Kniest dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
platyspondylic dysplasia, Torrance type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
spondyloepimetaphyseal dysplasia, Strudwick type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
spondyloepiphyseal dysplasia congenita
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
spondyloepiphyseal dysplasia with metatarsal shortening
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
spondylometaphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spondyloperipheral dysplasia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Stickler syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Illumina, Orphanet, Genomics England PanelApp
Stickler syndrome, type I, nonsyndromic ocular
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
avascular necrosis of femoral head, primary, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Legg-Calve-Perthes disease
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
otospondylomegaepiphyseal dysplasia, autosomal recessive
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
spondyloepiphyseal dysplasia, Stanescu type
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal dominant rhegmatogenous retinal detachment
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dysspondyloenchondromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial avascular necrosis of femoral head
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypochondrogenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multiple epiphyseal dysplasia, Beighton type
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
spondylometaphyseal dysplasia, Schmidt type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
otospondylomegaepiphyseal dysplasia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
vitreoretinopathy with phalangeal epiphyseal dysplasia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

COL2A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5 link	c.86-915C>A		intron_variant	Intron 1 of 53	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
COL2A1	ENST00000380518.8 link	c.86-915C>A	intron_variant	Intron 1 of 53	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7 link	c.86-2609C>A	intron_variant	Intron 1 of 52	1		ENSP00000338213.6
COL2A1	ENST00000474996.6 link	n.268C>A	non_coding_transcript_exon_variant	Exon 2 of 8	3
COL2A1	ENST00000490609.2 link	n.319-915C>A	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45637

AN:

152050

Hom.:

8078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.492

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.165

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.265

GnomAD4 exome

AF:

0.217

AC:

AN:

Hom.:

Cov.:

AF XY:

0.225

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.263

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.300

AC:

45680

AN:

152168

Hom.:

8089

Cov.:

AF XY:

0.295

AC XY:

21954

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.492

AC:

20416

AN:

41484

American (AMR)

AF:

0.170

AC:

2595

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

545

AN:

3472

East Asian (EAS)

AF:

0.165

AC:

856

AN:

5178

South Asian (SAS)

AF:

0.171

AC:

826

AN:

4828

European-Finnish (FIN)

AF:

0.256

AC:

2718

AN:

10604

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.248

AC:

16876

AN:

67984

Other (OTH)

AF:

0.262

AC:

554

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1557

3114

4670

6227

7784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.244

Hom.:

8030

Bravo

AF:

0.302

Asia WGS

AF:

0.191

AC:

663

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.3

(source)

DANN

Benign

0.85

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over