rs2276454

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001844.5(COL2A1):c.2295C>T(p.Gly765Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,609,760 control chromosomes in the GnomAD database, including 133,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G765G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.38 ( 11563 hom., cov: 33)

Exomes 𝑓: 0.40 ( 121588 hom. )

Consequence

COL2A1
NM_001844.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.142

Publications

42 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
COL2A1-related spondyloepiphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dysplasia of the proximal femoral epiphyses
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Kniest dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
platyspondylic dysplasia, Torrance type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
spondyloepimetaphyseal dysplasia, Strudwick type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
spondyloepiphyseal dysplasia congenita
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
spondyloepiphyseal dysplasia with metatarsal shortening
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
spondylometaphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spondyloperipheral dysplasia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Stickler syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Illumina
Stickler syndrome, type I, nonsyndromic ocular
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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: Orphanet, Labcorp Genetics (formerly Invitae)
otospondylomegaepiphyseal dysplasia, autosomal recessive
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
spondyloepiphyseal dysplasia, Stanescu type
Inheritance: Unknown, 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: Labcorp Genetics (formerly Invitae), Orphanet
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:

LOC105369752 (HGNC:):

LOC105369752 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-47982508-G-A is Benign according to our data. Variant chr12-47982508-G-A is described in ClinVar as Benign. ClinVar VariationId is 258225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.142 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001844.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	NM_001844.5	MANE Select	c.2295C>T	p.Gly765Gly	synonymous	Exon 34 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.2088C>T	p.Gly696Gly	synonymous	Exon 33 of 53	NP_149162.2	P02458-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.2295C>T	p.Gly765Gly	synonymous	Exon 34 of 54	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7	TSL:1	c.2088C>T	p.Gly696Gly	synonymous	Exon 33 of 53	ENSP00000338213.6	P02458-1
COL2A1	ENST00000928357.1		c.2298C>T	p.Gly766Gly	synonymous	Exon 34 of 54	ENSP00000598416.1

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58356

AN:

151954

Hom.:

11564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.474

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.403

Gnomad OTH

AF:

0.405

GnomAD2 exomes

AF:

0.390

AC:

96877

AN:

248278

AF XY:

0.402

show subpopulations

Gnomad AFR exome

AF:

0.346

Gnomad AMR exome

AF:

0.246

Gnomad ASJ exome

AF:

0.388

Gnomad EAS exome

AF:

0.598

Gnomad FIN exome

AF:

0.337

Gnomad NFE exome

AF:

0.394

Gnomad OTH exome

AF:

0.411

GnomAD4 exome

AF:

0.404

AC:

588640

AN:

1457688

Hom.:

121588

Cov.:

AF XY:

0.407

AC XY:

295367

AN XY:

725366

show subpopulations

African (AFR)

AF:

0.346

AC:

11553

AN:

33420

American (AMR)

AF:

0.257

AC:

11500

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.394

AC:

10283

AN:

26110

East Asian (EAS)

AF:

0.567

AC:

22495

AN:

39680

South Asian (SAS)

AF:

0.467

AC:

40273

AN:

86166

European-Finnish (FIN)

AF:

0.338

AC:

17974

AN:

53150

Middle Eastern (MID)

AF:

0.512

AC:

2952

AN:

5762

European-Non Finnish (NFE)

AF:

0.403

AC:

446279

AN:

1108458

Other (OTH)

AF:

0.420

AC:

25331

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

16722

33443

50165

66886

83608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13904

27808

41712

55616

69520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.384

AC:

58368

AN:

152072

Hom.:

11563

Cov.:

AF XY:

0.381

AC XY:

28306

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.346

AC:

14362

AN:

41508

American (AMR)

AF:

0.340

AC:

5204

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1374

AN:

3466

East Asian (EAS)

AF:

0.592

AC:

3057

AN:

5162

South Asian (SAS)

AF:

0.475

AC:

2290

AN:

4824

European-Finnish (FIN)

AF:

0.327

AC:

3463

AN:

10584

Middle Eastern (MID)

AF:

0.490

AC:

144

AN:

294

European-Non Finnish (NFE)

AF:

0.403

AC:

27359

AN:

67912

Other (OTH)

AF:

0.401

AC:

847

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1819

3639

5458

7278

9097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.394

Hom.:

33970

Bravo

AF:

0.382

Asia WGS

AF:

0.452

AC:

1571

AN:

3478

EpiCase

AF:

0.421

EpiControl

AF:

0.422

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (2)

Stickler syndrome type 1 (1)

Type II Collagenopathies (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.8

(source)

DANN

Benign

0.65

PhyloP100

0.14

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over