Genetic Variant COL9A2:p.Val581Phe (chr1-40302672-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001852.4(COL9A2):c.1741G>T(p.Val581Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V581I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3508662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1741G>T	p.Val581Phe	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>T	p.Val581Phe	missense_variant	Exon 30 of 32	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 link	n.2044G>T		non_coding_transcript_exon_variant	Exon 29 of 31	1
COL9A2	ENST00000427563.1 link	n.497G>T		non_coding_transcript_exon_variant	Exon 7 of 7	3
COL9A2	ENST00000466267.1 link	n.706G>T		non_coding_transcript_exon_variant	Exon 10 of 11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000449

AC:

AN:

222764

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000596

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33084

American (AMR)

AF:

0.00

AC:

AN:

43402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25854

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38904

South Asian (SAS)

AF:

0.00

AC:

AN:

83932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4884

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106954

Other (OTH)

AF:

0.00

AC:

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.14

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.72

M_CAP

Benign

0.061

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.80

PhyloP100

1.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.30

Sift

Benign

0.17

Sift4G

Benign

0.53

Polyphen

1.0

Vest4

0.31

MutPred

0.36

Loss of MoRF binding (P = 0.0884);

MVP

0.95

MPC

0.95

ClinPred

0.74

GERP RS

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.20

gMVP

0.75

Mutation Taster

=77/23

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over