rs12077871

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_001852.4(COL9A2):c.976C>T(p.Gln326*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,614,022 control chromosomes in the GnomAD database, including 939 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.040 ( 276 hom., cov: 32)

Exomes 𝑓: 0.011 ( 663 hom. )

Consequence

COL9A2
NM_001852.4 stop_gained

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.07

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
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 -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 1-40307478-G-A is Benign according to our data. Variant chr1-40307478-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001852.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	NM_001852.4	MANE Select	c.976C>T	p.Gln326*	stop_gained	Exon 19 of 32	NP_001843.1	Q14055

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.976C>T	p.Gln326*	stop_gained	Exon 19 of 32	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5	TSL:1	n.1279C>T		non_coding_transcript_exon	Exon 18 of 31
COL9A2	ENST00000869268.1		c.976C>T	p.Gln326*	stop_gained	Exon 19 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6075

AN:

152158

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0443

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0368

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0312

AC:

7822

AN:

250928

AF XY:

0.0273

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0698

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.00216

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0115

AC:

16809

AN:

1461746

Hom.:

663

Cov.:

AF XY:

0.0115

AC XY:

8352

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.110

AC:

3677

AN:

33454

American (AMR)

AF:

0.0652

AC:

2913

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26136

East Asian (EAS)

AF:

0.116

AC:

4599

AN:

39694

South Asian (SAS)

AF:

0.0314

AC:

2705

AN:

86238

European-Finnish (FIN)

AF:

0.0123

AC:

658

AN:

53416

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000939

AC:

1044

AN:

1111972

Other (OTH)

AF:

0.0186

AC:

1122

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

934

1868

2801

3735

4669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.0400

AC:

6085

AN:

152276

Hom.:

276

Cov.:

AF XY:

0.0399

AC XY:

2969

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.105

AC:

4368

AN:

41528

American (AMR)

AF:

0.0445

AC:

681

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.109

AC:

561

AN:

5170

South Asian (SAS)

AF:

0.0369

AC:

178

AN:

4830

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68036

Other (OTH)

AF:

0.0364

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

281

561

842

1122

1403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0160

Hom.:

411

Bravo

AF:

0.0465

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0906

AC:

399

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0317

AC:

3849

Asia WGS

AF:

0.0610

AC:

215

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Epiphyseal dysplasia, multiple, 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.83

PhyloP100

2.1

Vest4

0.74

GERP RS

3.9

Mutation Taster

=139/61

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over