NM_001852.4:c.630+13G>T

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.630+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,654 control chromosomes in the GnomAD database, including 24,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1917 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23065 hom. )

Consequence

COL9A2
NM_001852.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0370

Publications

12 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=-0.68).

BP6

Variant 1-40311080-C-A is Benign according to our data. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311080-C-A is described in CliVar as Benign. Clinvar id is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.630+13G>T		intron_variant	Intron 12 of 31	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL9A2	ENST00000372748.8 link	c.630+13G>T	intron_variant	Intron 12 of 31	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 link	n.933+13G>T	intron_variant	Intron 11 of 30	1
COL9A2	ENST00000417105.6 link	c.348+13G>T	intron_variant	Intron 12 of 13	5		ENSP00000388493.2	H0Y409
COL9A2	ENST00000488463.6 link	n.681+13G>T	intron_variant	Intron 11 of 13	5

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21272

AN:

152082

Hom.:

1915

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0532

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.412

Gnomad SAS

AF:

0.0977

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.122

GnomAD2 exomes

AF:

0.174

AC:

43816

AN:

251264

AF XY:

0.168

show subpopulations

Gnomad AFR exome

AF:

0.0548

Gnomad AMR exome

AF:

0.248

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.385

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.160

GnomAD4 exome

AF:

0.168

AC:

245050

AN:

1461454

Hom.:

23065

Cov.:

AF XY:

0.166

AC XY:

120408

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.0497

AC:

1662

AN:

33468

American (AMR)

AF:

0.243

AC:

10857

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3583

AN:

26132

East Asian (EAS)

AF:

0.431

AC:

17091

AN:

39698

South Asian (SAS)

AF:

0.0987

AC:

8508

AN:

86244

European-Finnish (FIN)

AF:

0.187

AC:

9969

AN:

53418

Middle Eastern (MID)

AF:

0.0818

AC:

456

AN:

5576

European-Non Finnish (NFE)

AF:

0.165

AC:

183126

AN:

1111832

Other (OTH)

AF:

0.162

AC:

9798

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12393

24786

37180

49573

61966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6664

13328

19992

26656

33320

<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:

0.140

AC:

21274

AN:

152200

Hom.:

1917

Cov.:

AF XY:

0.141

AC XY:

10462

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0532

AC:

2209

AN:

41552

American (AMR)

AF:

0.201

AC:

3074

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

470

AN:

3470

East Asian (EAS)

AF:

0.412

AC:

2125

AN:

5152

South Asian (SAS)

AF:

0.0971

AC:

468

AN:

4818

European-Finnish (FIN)

AF:

0.178

AC:

1882

AN:

10602

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.156

AC:

10591

AN:

67986

Other (OTH)

AF:

0.121

AC:

255

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

896

1792

2687

3583

4479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.136

Hom.:

955

Bravo

AF:

0.141

Asia WGS

AF:

0.228

AC:

793

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 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. -

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 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

-0.68

CADD

Benign

7.7

(source)

DANN

Benign

0.86

PhyloP100

-0.037

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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