rs2228564

Positions:

• chr1-40307477-T-A
• chr1-40307477-T-C
• chr1-40307477-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The ENST00000372748.8(COL9A2):​c.977A>T​(p.Gln326Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. Q326R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL9A2 ENST00000372748.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.555

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1517891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.977A>T	p.Gln326Leu	missense_variant	19/32	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.977A>T	p.Gln326Leu	missense_variant	19/32	1	NM_001852.4	ENSP00000361834	P1
COL9A2	ENST00000482722.5	n.1280A>T		non_coding_transcript_exon_variant	18/31	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.29
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.024	B
Vest4		0.30
MutPred		0.26		Gain of catalytic residue at Q326 (P = 0.0953);
MVP		0.59
MPC		0.25
ClinPred		0.28	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs2228564; hg19: chr1-40773149;