rs373264436

Variant names:

• chr1-40303808-T-C
• rs373264436
• NM_001852.4:c.1400A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-40303808-T-C
• chr1-40303808-T-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_001852.4(COL9A2):​c.1400A>G​(p.Gln467Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000262 in 1,564,664 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q467E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: COL9A2 NM_001852.4 missense, splice_region
• Scores: Splicing: ADA: 0.9877
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 1-40303808-T-C is Benign according to our data. Variant chr1-40303808-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297297.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001852.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	NM_001852.4	MANE Select	c.1400A>G	p.Gln467Arg	missense splice_region	Exon 27 of 32	NP_001843.1	Q14055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.1400A>G	p.Gln467Arg	missense splice_region	Exon 27 of 32	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1703A>G		splice_region non_coding_transcript_exon	Exon 26 of 31
	COL9A2	ENST00000869268.1		c.1484A>G	p.Gln495Arg	missense splice_region	Exon 27 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 42 AN: 151814 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000482 AC: 79 AN: 163758 AF XY: 0.000507

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00667

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000260 AC: 368 AN: 1412850 Hom.: 3 Cov.: 34 AF XY: 0.000292 AC XY: 204 AN XY: 698230

African (AFR) AF: 0.00 AC: 0 AN: 32686

American (AMR) AF: 0.000190 AC: 7 AN: 36882

Ashkenazi Jewish (ASJ) AF: 0.00622 AC: 157 AN: 25258

East Asian (EAS) AF: 0.00 AC: 0 AN: 37580

South Asian (SAS) AF: 0.00 AC: 0 AN: 80300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4846

European-Non Finnish (NFE) AF: 0.000157 AC: 171 AN: 1088202

Other (OTH) AF: 0.000564 AC: 33 AN: 58492

GnomAD4 genome AF: 0.000277 AC: 42 AN: 151814 Hom.: 1 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74162

African (AFR) AF: 0.0000242 AC: 1 AN: 41286

American (AMR) AF: 0.000262 AC: 4 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67918

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.000807 Hom.: 1

Bravo AF: 0.000249

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.000252 AC: 28

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	COL9A2-related disorder (1)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)
-	1	-	Epiphyseal dysplasia, multiple, 2;C3280342:Stickler syndrome, type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0050	N
PhyloP100		3.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Benign	0.13	T
Sift4G	Uncertain	0.036	D
Polyphen		0.48	P
Vest4		0.46
MVP		0.83
MPC		0.37
ClinPred		0.030	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.67
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373264436; hg19: chr1-40769480;