1-40301196-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001852.4(COL9A2):c.2056A>G(p.Ile686Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I686I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: COL9A2 NM_001852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0959512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.2056A>G	p.Ile686Val	missense_variant	32/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.2056A>G	p.Ile686Val	missense_variant	32/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.2359A>G		non_coding_transcript_exon_variant	31/31	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461348 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL9A2 protein function. ClinVar contains an entry for this variant (Variation ID: 1511987). This variant has not been reported in the literature in individuals affected with COL9A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 686 of the COL9A2 protein (p.Ile686Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-0.51	N
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.29
Sift	Benign	0.24	T
Sift4G	Benign	0.85	T
Polyphen		0.27	B
Vest4		0.10
MutPred		0.18		Loss of catalytic residue at I686 (P = 0.0845);
MVP		0.63
MPC		0.29
ClinPred		0.63	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.063
gMVP		0.65

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: rs1643908954; hg19: chr1-40766868;