12-47985117-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001844.5(COL2A1):c.1735-24T>C variant causes a intron change. The variant allele was found at a frequency of 0.063 in 1,582,242 control chromosomes in the GnomAD database, including 3,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.051 ( 247 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3405 hom. )

Consequence

COL2A1
NM_001844.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.74

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 12-47985117-A-G is Benign according to our data. Variant chr12-47985117-A-G is described in ClinVar as Benign. ClinVar VariationId is 258216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0718 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.1735-24T>C		intron	N/A	NP_001835.3
	COL2A1	NM_033150.3		c.1528-24T>C		intron	N/A	NP_149162.2	P02458-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.1735-24T>C	intron	N/A	ENSP00000369889.3	P02458-2
COL2A1	ENST00000337299.7	TSL:1	c.1528-24T>C	intron	N/A	ENSP00000338213.6	P02458-1
COL2A1	ENST00000928357.1		c.1738-24T>C	intron	N/A	ENSP00000598416.1

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7685

AN:

152078

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0269

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0292

Gnomad ASJ

AF:

0.0113

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.0861

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0735

Gnomad OTH

AF:

0.0455

GnomAD2 exomes

AF:

0.0482

AC:

11495

AN:

238680

AF XY:

0.0476

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.000282

Gnomad FIN exome

AF:

0.0889

Gnomad NFE exome

AF:

0.0740

Gnomad OTH exome

AF:

0.0500

GnomAD4 exome

AF:

0.0643

AC:

91991

AN:

1430046

Hom.:

3405

Cov.:

AF XY:

0.0628

AC XY:

44728

AN XY:

712670

show subpopulations

African (AFR)

AF:

0.0230

AC:

756

AN:

32858

American (AMR)

AF:

0.0210

AC:

924

AN:

44086

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

330

AN:

25810

East Asian (EAS)

AF:

0.000432

AC:

AN:

39396

South Asian (SAS)

AF:

0.0115

AC:

973

AN:

84964

European-Finnish (FIN)

AF:

0.0879

AC:

4612

AN:

52466

Middle Eastern (MID)

AF:

0.0185

AC:

106

AN:

5718

European-Non Finnish (NFE)

AF:

0.0747

AC:

81028

AN:

1085420

Other (OTH)

AF:

0.0547

AC:

3245

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

4231

8463

12694

16926

21157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2878

5756

8634

11512

14390

<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:

0.0505

AC:

7691

AN:

152196

Hom.:

247

Cov.:

AF XY:

0.0500

AC XY:

3717

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0270

AC:

1123

AN:

41536

American (AMR)

AF:

0.0291

AC:

446

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

AN:

3466

East Asian (EAS)

AF:

0.000775

AC:

AN:

5160

South Asian (SAS)

AF:

0.0133

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0861

AC:

912

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0735

AC:

4996

AN:

67996

Other (OTH)

AF:

0.0450

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

373

746

1119

1492

1865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0596

Hom.:

215

Bravo

AF:

0.0436

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

3.7

BranchPoint Hunter

5.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over