rs2228565

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.737C>T(p.Thr246Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,614,028 control chromosomes in the GnomAD database, including 1,056 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T246T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.021 ( 61 hom., cov: 32)

Exomes 𝑓: 0.033 ( 995 hom. )

Consequence

COL9A2
NM_001852.4 missense, splice_region

Scores

Splicing: ADA: 0.0001059

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.167

Publications

13 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), G2P, Genomics England PanelApp, Ambry Genetics
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

new If you want to explore the variant's impact on the transcript NM_001852.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0078905225).

BP6

Variant 1-40310265-G-A is Benign according to our data. Variant chr1-40310265-G-A is described in ClinVar as Benign. ClinVar VariationId is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3261/152252) while in subpopulation NFE AF = 0.0339 (2304/67998). AF 95% confidence interval is 0.0327. There are 61 homozygotes in GnomAd4. There are 1536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 61 AR,AD gene

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.737C>T	p.Thr246Met	missense splice_region	Exon 14 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.737C>T	p.Thr246Met	missense splice_region	Exon 14 of 32	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5	TSL:1	n.1040C>T		splice_region non_coding_transcript_exon	Exon 13 of 31
COL9A2	ENST00000869268.1		c.737C>T	p.Thr246Met	missense splice_region	Exon 14 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3262

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0339

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0218

AC:

5493

AN:

251406

AF XY:

0.0219

show subpopulations

Gnomad AFR exome

AF:

0.00708

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0337

Gnomad OTH exome

AF:

0.0241

GnomAD4 exome

AF:

0.0331

AC:

48426

AN:

1461776

Hom.:

995

Cov.:

AF XY:

0.0323

AC XY:

23512

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00523

AC:

175

AN:

33480

American (AMR)

AF:

0.0105

AC:

469

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00654

AC:

171

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00538

AC:

464

AN:

86256

European-Finnish (FIN)

AF:

0.0367

AC:

1962

AN:

53390

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0389

AC:

43281

AN:

1111926

Other (OTH)

AF:

0.0308

AC:

1858

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

2656

5313

7969

10626

13282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1658

3316

4974

6632

8290

<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:

0.0214

AC:

3261

AN:

152252

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1536

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00631

AC:

262

AN:

41552

American (AMR)

AF:

0.0107

AC:

163

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00497

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0388

AC:

411

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0339

AC:

2304

AN:

67998

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

170

340

510

680

850

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:

0.0283

Hom.:

219

Bravo

AF:

0.0202

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0300

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Connective tissue disorder (1)

Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.18

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.040

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.0

PhyloP100

-0.17

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Benign

0.17

Varity_R

0.026

gMVP

0.21

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.044

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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