chr1-40307451-G-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.1003C>G(p.Leu335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,598 control chromosomes in the GnomAD database, including 12,060 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. L335I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.098 ( 766 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11294 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.394

Publications

28 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=0.0024698377).

BP6

Variant 1-40307451-G-C is Benign according to our data. Variant chr1-40307451-G-C is described in ClinVar as Benign. ClinVar VariationId is 258364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1003C>G	p.Leu335Val	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.1003C>G	p.Leu335Val	missense_variant	Exon 19 of 32	1	NM_001852.4	ENSP00000361834.3		Q14055
COL9A2	ENST00000482722.5 link	n.1306C>G		non_coding_transcript_exon_variant	Exon 18 of 31	1

Frequencies

GnomAD3 genomes

AF:

0.0984

AC:

14978

AN:

152186

Hom.:

768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0667

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0985

Gnomad ASJ

AF:

0.0541

Gnomad EAS

AF:

0.0993

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0843

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.0979

GnomAD2 exomes

AF:

0.104

AC:

26061

AN:

250194

AF XY:

0.106

show subpopulations

Gnomad AFR exome

AF:

0.0651

Gnomad AMR exome

AF:

0.0812

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.0842

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.121

AC:

177507

AN:

1461294

Hom.:

11294

Cov.:

AF XY:

0.120

AC XY:

87578

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.0617

AC:

2067

AN:

33478

American (AMR)

AF:

0.0841

AC:

3757

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.0627

AC:

1638

AN:

26128

East Asian (EAS)

AF:

0.0876

AC:

3477

AN:

39692

South Asian (SAS)

AF:

0.112

AC:

9645

AN:

86186

European-Finnish (FIN)

AF:

0.0849

AC:

4531

AN:

53386

Middle Eastern (MID)

AF:

0.0640

AC:

369

AN:

5768

European-Non Finnish (NFE)

AF:

0.131

AC:

145221

AN:

1111660

Other (OTH)

AF:

0.113

AC:

6802

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

8220

16441

24661

32882

41102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5360

10720

16080

21440

26800

<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:

0.0984

AC:

14982

AN:

152304

Hom.:

766

Cov.:

AF XY:

0.0956

AC XY:

7124

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0665

AC:

2764

AN:

41562

American (AMR)

AF:

0.0987

AC:

1511

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0541

AC:

188

AN:

3472

East Asian (EAS)

AF:

0.0991

AC:

514

AN:

5186

South Asian (SAS)

AF:

0.111

AC:

538

AN:

4832

European-Finnish (FIN)

AF:

0.0843

AC:

895

AN:

10612

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8227

AN:

68014

Other (OTH)

AF:

0.101

AC:

213

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

732

1464

2197

2929

3661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.108

Hom.:

775

Bravo

AF:

0.0974

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.139

AC:

536

ESP6500AA

AF:

0.0738

AC:

325

ESP6500EA

AF:

0.113

AC:

974

ExAC

AF:

0.104

AC:

12622

Asia WGS

AF:

0.0980

AC:

342

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Oct 06, 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

0.086

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.079

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.4

PhyloP100

0.39

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.84

REVEL

Benign

0.24

Sift

Benign

0.050

Sift4G

Benign

0.093

Polyphen

0.82

Vest4

0.12

MPC

0.68

ClinPred

0.015

GERP RS

3.0

Varity_R

0.13

gMVP

0.17

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

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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