rs373264436

chr1-40303808-T-Achr1-40303808-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.1400A>T	p.Gln467Leu	missense_variant, splice_region_variant	27/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.1400A>T	p.Gln467Leu	missense_variant, splice_region_variant	27/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.1703A>T		splice_region_variant, non_coding_transcript_exon_variant	26/31	1
COL9A2	ENST00000427563.1	n.211A>T		splice_region_variant, non_coding_transcript_exon_variant	5/7	3
COL9A2	ENST00000466267.1	n.365A>T		splice_region_variant, non_coding_transcript_exon_variant	7/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 2 AN: 163758 Hom.: 0 AF XY: 0.0000113 AC XY: 1 AN XY: 88706

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 SAS 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: 2 AN: 1412850 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 698230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000542

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Benign	0.81
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.035	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.36		Gain of methylation at R471 (P = 0.0721);
MVP		0.89
MPC		0.81
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.33
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs373264436; hg19: chr1-40769480;