chr1-40304784-A-T

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.1161+10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,549,974 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 49 hom., cov: 33)

Exomes 𝑓: 0.021 ( 384 hom. )

Consequence

COL9A2
NM_001852.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.670

Publications

4 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=-0.52).

BP6

Variant 1-40304784-A-T is Benign according to our data. Variant chr1-40304784-A-T is described in ClinVar as Benign. ClinVar VariationId is 258367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.021 (3197/152310) while in subpopulation SAS AF = 0.0329 (159/4830). AF 95% confidence interval is 0.0287. There are 49 homozygotes in GnomAd4. There are 1626 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1161+10T>A		intron_variant	Intron 22 of 31	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL9A2	ENST00000372748.8 link	c.1161+10T>A	intron_variant	Intron 22 of 31	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 link	n.1464+10T>A	intron_variant	Intron 21 of 30	1
COL9A2	ENST00000466267.1 link	n.126+10T>A	intron_variant	Intron 2 of 10	5

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3196

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0261

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.0256

Gnomad SAS

AF:

0.0329

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0285

AC:

4429

AN:

155580

AF XY:

0.0283

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0503

Gnomad ASJ exome

AF:

0.0395

Gnomad EAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.0244

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0209

AC:

29208

AN:

1397664

Hom.:

384

Cov.:

AF XY:

0.0216

AC XY:

14900

AN XY:

689392

show subpopulations

African (AFR)

AF:

0.0132

AC:

417

AN:

31570

American (AMR)

AF:

0.0462

AC:

1649

AN:

35656

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

1020

AN:

25128

East Asian (EAS)

AF:

0.0335

AC:

1197

AN:

35738

South Asian (SAS)

AF:

0.0347

AC:

2747

AN:

79168

European-Finnish (FIN)

AF:

0.0249

AC:

1210

AN:

48602

Middle Eastern (MID)

AF:

0.0152

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.0182

AC:

19677

AN:

1078194

Other (OTH)

AF:

0.0208

AC:

1205

AN:

57960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1529

3058

4588

6117

7646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

714

1428

2142

2856

3570

<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:

0.0210

AC:

3197

AN:

152310

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

1626

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0153

AC:

636

AN:

41578

American (AMR)

AF:

0.0260

AC:

398

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

141

AN:

3472

East Asian (EAS)

AF:

0.0257

AC:

133

AN:

5176

South Asian (SAS)

AF:

0.0329

AC:

159

AN:

4830

European-Finnish (FIN)

AF:

0.0230

AC:

244

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1442

AN:

68012

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

163

327

490

654

817

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:

0.0188

Hom.:

Bravo

AF:

0.0202

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 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:3

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

- -

Mar 11, 2019

Athena Diagnostics

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. -

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.1

(source)

DANN

Benign

0.81

PhyloP100

0.67

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

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