Genetic Variant COL9A2:p.Gln467Leu (chr1-40303808-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001852.4(COL9A2):c.1400A>T(p.Gln467Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000142 in 1,412,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. Q467R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL9A2
NM_001852.4 missense, splice_region

Scores

Splicing: ADA: 0.9756

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.63

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1400A>T	p.Gln467Leu	missense_variant, splice_region_variant	Exon 27 of 32	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL9A2	ENST00000372748.8 link	c.1400A>T	p.Gln467Leu	missense_variant, splice_region_variant	Exon 27 of 32	1	NM_001852.4	ENSP00000361834.3
COL9A2	ENST00000482722.5 link	n.1703A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 26 of 31	1
COL9A2	ENST00000427563.1 link	n.211A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 7	3
COL9A2	ENST00000466267.1 link	n.365A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

163758

AF XY:

0.0000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1412850

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32686

American (AMR)

AF:

0.0000542

AC:

AN:

36882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25258

East Asian (EAS)

AF:

0.00

AC:

AN:

37580

South Asian (SAS)

AF:

0.00

AC:

AN:

80300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4846

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088202

Other (OTH)

AF:

0.00

AC:

AN:

58492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

0.19

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.035

PhyloP100

3.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.47

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.024

Vest4

0.33

ClinPred

0.65

GERP RS

4.5

Varity_R

0.33

gMVP

0.68

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.59

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over