1-40310265-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001852.4(COL9A2):c.737C>T(p.Thr246Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,614,028 control chromosomes in the GnomAD database, including 1,056 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T246T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.021 ( 61 hom., cov: 32)

Exomes 𝑓: 0.033 ( 995 hom. )

Consequence

COL9A2
NM_001852.4 missense, splice_region

Scores

Splicing: ADA: 0.0001059

Clinical Significance

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

Conservation

PhyloP100: -0.167

Publications

13 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=0.0078905225).

BP6

Variant 1-40310265-G-A is Benign according to our data. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in CliVar as Benign. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3261/152252) while in subpopulation NFE AF = 0.0339 (2304/67998). AF 95% confidence interval is 0.0327. There are 61 homozygotes in GnomAd4. There are 1536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 61 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.737C>T	p.Thr246Met	missense_variant, splice_region_variant	Exon 14 of 32	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL9A2	ENST00000372748.8 link	c.737C>T	p.Thr246Met	missense_variant, splice_region_variant	Exon 14 of 32	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 link	n.1040C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 31	1
COL9A2	ENST00000488463.6 link	n.788C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 14	5
COL9A2	ENST00000417105.6 link	c.*25C>T		downstream_gene_variant		5		ENSP00000388493.2	H0Y409

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3262

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0339

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0218

AC:

5493

AN:

251406

AF XY:

0.0219

show subpopulations

Gnomad AFR exome

AF:

0.00708

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0337

Gnomad OTH exome

AF:

0.0241

GnomAD4 exome

AF:

0.0331

AC:

48426

AN:

1461776

Hom.:

995

Cov.:

AF XY:

0.0323

AC XY:

23512

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00523

AC:

175

AN:

33480

American (AMR)

AF:

0.0105

AC:

469

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00654

AC:

171

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00538

AC:

464

AN:

86256

European-Finnish (FIN)

AF:

0.0367

AC:

1962

AN:

53390

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0389

AC:

43281

AN:

1111926

Other (OTH)

AF:

0.0308

AC:

1858

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

2656

5313

7969

10626

13282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1658

3316

4974

6632

8290

<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:

0.0214

AC:

3261

AN:

152252

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1536

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00631

AC:

262

AN:

41552

American (AMR)

AF:

0.0107

AC:

163

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00497

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0388

AC:

411

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0339

AC:

2304

AN:

67998

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

170

340

510

680

850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0283

Hom.:

219

Bravo

AF:

0.0202

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0345

AC:

297

ExAC

AF:

0.0222

AC:

2694

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0300

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 11, 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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Oct 12, 2018

Athena Diagnostics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

Connective tissue disorder

Benign:1

Feb 12, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.18

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.040

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.0

PhyloP100

-0.17

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Benign

0.17

Polyphen

0.0020

Vest4

0.17

MPC

0.77

ClinPred

0.014

GERP RS

-9.3

Varity_R

0.026

gMVP

0.21

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.044

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