chr1-40304111-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001852.4(COL9A2):c.1288-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 1,548,576 control chromosomes in the GnomAD database, including 1,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 136 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1287 hom. )

Consequence

COL9A2
NM_001852.4 intron

Scores

Splicing: ADA: 0.00001605

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.35

Publications

3 publications found

Variant links:

Genes affected

COL9A2 (HGNC:2218): (collagen type IX alpha 2 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

COL9A2 Gene-Disease associations (from GenCC):

epiphyseal dysplasia, multiple, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Stickler syndrome, type 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
multiple epiphyseal dysplasia due to collagen 9 anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Stickler syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Stickler syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

COL9A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-40304111-G-A is Benign according to our data. Variant chr1-40304111-G-A is described in ClinVar as Benign. ClinVar VariationId is 258370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1288-12C>T		intron_variant	Intron 24 of 31	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
COL9A2	ENST00000372748.8 link	c.1288-12C>T	intron_variant	Intron 24 of 31	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5 link	n.1591-12C>T	intron_variant	Intron 23 of 30	1
COL9A2	ENST00000427563.1 link	n.99-12C>T	intron_variant	Intron 2 of 6	3
COL9A2	ENST00000466267.1 link	n.253-12C>T	intron_variant	Intron 4 of 10	5

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4529

AN:

152082

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00782

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.0966

Gnomad FIN

AF:

0.0273

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0515

AC:

8017

AN:

155602

AF XY:

0.0524

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0562

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.0296

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0382

GnomAD4 exome

AF:

0.0336

AC:

46945

AN:

1396376

Hom.:

1287

Cov.:

AF XY:

0.0348

AC XY:

23939

AN XY:

688640

show subpopulations

African (AFR)

AF:

0.00723

AC:

233

AN:

32220

American (AMR)

AF:

0.0531

AC:

1917

AN:

36132

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

439

AN:

24886

East Asian (EAS)

AF:

0.146

AC:

5382

AN:

36910

South Asian (SAS)

AF:

0.0803

AC:

6395

AN:

79594

European-Finnish (FIN)

AF:

0.0256

AC:

1120

AN:

43764

Middle Eastern (MID)

AF:

0.0332

AC:

173

AN:

5216

European-Non Finnish (NFE)

AF:

0.0271

AC:

29271

AN:

1079728

Other (OTH)

AF:

0.0348

AC:

2015

AN:

57926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2663

5327

7990

10654

13317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1262

2524

3786

5048

6310

<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:

0.0298

AC:

4533

AN:

152200

Hom.:

136

Cov.:

AF XY:

0.0315

AC XY:

2347

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.00780

AC:

324

AN:

41534

American (AMR)

AF:

0.0382

AC:

585

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.157

AC:

811

AN:

5156

South Asian (SAS)

AF:

0.0973

AC:

469

AN:

4822

European-Finnish (FIN)

AF:

0.0273

AC:

289

AN:

10604

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1864

AN:

67994

Other (OTH)

AF:

0.0266

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

217

434

651

868

1085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0146

Hom.:

Bravo

AF:

0.0297

Asia WGS

AF:

0.113

AC:

393

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 25, 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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 20, 2016

Eurofins Ntd Llc (ga)

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

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Epiphyseal dysplasia, multiple, 2

Benign:1

Jan 12, 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.34

(source)

DANN

Benign

0.64

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over