1-40307477-T-C

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.977A>G(p.Gln326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,613,126 control chromosomes in the GnomAD database, including 59,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q326W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.30 ( 7863 hom., cov: 32)

Exomes 𝑓: 0.25 ( 51452 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.555

Publications

55 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 (MetaRNN=3.5691442E-5).

BP6

Variant 1-40307477-T-C is Benign according to our data. Variant chr1-40307477-T-C is described in ClinVar as Benign. ClinVar VariationId is 258399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.977A>G	p.Gln326Arg	missense_variant	Exon 19 of 32	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8 link	c.977A>G	p.Gln326Arg	missense_variant	Exon 19 of 32	1	NM_001852.4	ENSP00000361834.3		Q14055
COL9A2	ENST00000482722.5 link	n.1280A>G		non_coding_transcript_exon_variant	Exon 18 of 31	1

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45539

AN:

151986

Hom.:

7827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.408

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.363

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.249

GnomAD2 exomes

AF:

0.304

AC:

76240

AN:

250534

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.481

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.600

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.215

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.249

AC:

363223

AN:

1461022

Hom.:

51452

Cov.:

AF XY:

0.248

AC XY:

180398

AN XY:

726830

show subpopulations

African (AFR)

AF:

0.420

AC:

14043

AN:

33452

American (AMR)

AF:

0.466

AC:

20789

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5325

AN:

26126

East Asian (EAS)

AF:

0.652

AC:

25869

AN:

39684

South Asian (SAS)

AF:

0.288

AC:

24841

AN:

86218

European-Finnish (FIN)

AF:

0.245

AC:

13105

AN:

53394

Middle Eastern (MID)

AF:

0.175

AC:

1009

AN:

5766

European-Non Finnish (NFE)

AF:

0.218

AC:

242476

AN:

1111388

Other (OTH)

AF:

0.261

AC:

15766

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

14569

29138

43708

58277

72846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8814

17628

26442

35256

44070

<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:

0.300

AC:

45640

AN:

152104

Hom.:

7863

Cov.:

AF XY:

0.303

AC XY:

22540

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.409

AC:

16979

AN:

41486

American (AMR)

AF:

0.363

AC:

5549

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

695

AN:

3472

East Asian (EAS)

AF:

0.620

AC:

3192

AN:

5150

South Asian (SAS)

AF:

0.305

AC:

1471

AN:

4820

European-Finnish (FIN)

AF:

0.234

AC:

2479

AN:

10576

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.213

AC:

14455

AN:

68004

Other (OTH)

AF:

0.251

AC:

531

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1559

3118

4678

6237

7796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.243

Hom.:

8220

Bravo

AF:

0.317

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.214

AC:

825

ESP6500AA

AF:

0.403

AC:

1777

ESP6500EA

AF:

0.214

AC:

1840

ExAC

AF:

0.301

AC:

36519

Asia WGS

AF:

0.472

AC:

1640

AN:

3478

EpiCase

AF:

0.208

EpiControl

AF:

0.200

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 29, 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. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

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

- -

Epiphyseal dysplasia, multiple, 2

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.12

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.21

MetaRNN

Benign

0.000036

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.95

PhyloP100

0.56

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.82

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.042

MPC

0.28

ClinPred

0.0022

GERP RS

5.0

Varity_R

0.12

gMVP

0.22

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over