1-40302672-C-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.1741G>A(p.Val581Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,600,116 control chromosomes in the GnomAD database, including 1,677 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 (★★).

Frequency

Genomes: 𝑓 0.065 ( 613 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1064 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.05

Publications

14 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=0.0013181865).

BP6

Variant 1-40302672-C-T is Benign according to our data. Variant chr1-40302672-C-T is described in ClinVar as Benign. ClinVar VariationId is 196620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1741G>A	p.Val581Ile	missense_variant	Exon 30 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.1741G>A	p.Val581Ile	missense_variant	Exon 30 of 32	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 link	n.2044G>A		non_coding_transcript_exon_variant	Exon 29 of 31	1
COL9A2	ENST00000427563.1 link	n.497G>A		non_coding_transcript_exon_variant	Exon 7 of 7	3
COL9A2	ENST00000466267.1 link	n.706G>A		non_coding_transcript_exon_variant	Exon 10 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.0645

AC:

9814

AN:

152050

Hom.:

608

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0418

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.0260

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0228

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0380

AC:

8454

AN:

222764

AF XY:

0.0345

show subpopulations

Gnomad AFR exome

AF:

0.168

Gnomad AMR exome

AF:

0.0590

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.0218

Gnomad FIN exome

AF:

0.0235

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0275

GnomAD4 exome

AF:

0.0257

AC:

37231

AN:

1447948

Hom.:

1064

Cov.:

AF XY:

0.0257

AC XY:

18504

AN XY:

719292

show subpopulations

African (AFR)

AF:

0.180

AC:

5944

AN:

33082

American (AMR)

AF:

0.0564

AC:

2446

AN:

43368

Ashkenazi Jewish (ASJ)

AF:

0.0408

AC:

1055

AN:

25852

East Asian (EAS)

AF:

0.0328

AC:

1277

AN:

38904

South Asian (SAS)

AF:

0.0353

AC:

2961

AN:

83926

European-Finnish (FIN)

AF:

0.0247

AC:

1268

AN:

51248

Middle Eastern (MID)

AF:

0.0236

AC:

115

AN:

4882

European-Non Finnish (NFE)

AF:

0.0183

AC:

20242

AN:

1106924

Other (OTH)

AF:

0.0322

AC:

1923

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2055

4109

6164

8218

10273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

830

1660

2490

3320

4150

<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:

0.0647

AC:

9849

AN:

152168

Hom.:

613

Cov.:

AF XY:

0.0651

AC XY:

4842

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.168

AC:

6963

AN:

41500

American (AMR)

AF:

0.0418

AC:

639

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0409

AC:

142

AN:

3472

East Asian (EAS)

AF:

0.0260

AC:

134

AN:

5150

South Asian (SAS)

AF:

0.0338

AC:

163

AN:

4824

European-Finnish (FIN)

AF:

0.0228

AC:

242

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0215

AC:

1461

AN:

67984

Other (OTH)

AF:

0.0458

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

444

889

1333

1778

2222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0365

Hom.:

1012

Bravo

AF:

0.0705

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.153

AC:

670

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0370

AC:

4465

Asia WGS

AF:

0.0640

AC:

223

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

- -

Feb 04, 2015

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 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:4

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

- -

Feb 15, 2019

Athena Diagnostics

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 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

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.091

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.74

PhyloP100

1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

0.020

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.59

Polyphen

0.48

Vest4

0.050

MPC

0.22

ClinPred

0.0034

GERP RS

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.038

gMVP

0.32

Mutation Taster

=99/1

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

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