NM_001852.4:c.977A>G

Variant names:

• chr1-40307477-T-C
• rs2228564
• NM_001852.4:c.977A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.977A>G​(p.Gln326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,613,126 control chromosomes in the GnomAD database, including 59,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q326W) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7863 hom., cov: 32)
  • Exomes 𝑓: 0.25 (51452 hom.)
• Consequence: COL9A2 NM_001852.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.555
• Publications: 55 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5691442E-5).
• BP6: Variant 1-40307477-T-C is Benign according to our data. Variant chr1-40307477-T-C is described in ClinVar as Benign. ClinVar VariationId is 258399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

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.977A>G	p.Gln326Arg	missense	Exon 19 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.977A>G	p.Gln326Arg	missense	Exon 19 of 32	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1280A>G		non_coding_transcript_exon	Exon 18 of 31
	COL9A2	ENST00000869268.1		c.977A>G	p.Gln326Arg	missense	Exon 19 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45539 AN: 151986 Hom.: 7827 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.304 AC: 76240 AN: 250534 AF XY: 0.290

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.249 AC: 363223 AN: 1461022 Hom.: 51452 Cov.: 37 AF XY: 0.248 AC XY: 180398 AN XY: 726830

African (AFR) AF: 0.420 AC: 14043 AN: 33452

American (AMR) AF: 0.466 AC: 20789 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5325 AN: 26126

East Asian (EAS) AF: 0.652 AC: 25869 AN: 39684

South Asian (SAS) AF: 0.288 AC: 24841 AN: 86218

European-Finnish (FIN) AF: 0.245 AC: 13105 AN: 53394

Middle Eastern (MID) AF: 0.175 AC: 1009 AN: 5766

European-Non Finnish (NFE) AF: 0.218 AC: 242476 AN: 1111388

Other (OTH) AF: 0.261 AC: 15766 AN: 60358

GnomAD4 genome AF: 0.300 AC: 45640 AN: 152104 Hom.: 7863 Cov.: 32 AF XY: 0.303 AC XY: 22540 AN XY: 74356

African (AFR) AF: 0.409 AC: 16979 AN: 41486

American (AMR) AF: 0.363 AC: 5549 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3472

East Asian (EAS) AF: 0.620 AC: 3192 AN: 5150

South Asian (SAS) AF: 0.305 AC: 1471 AN: 4820

European-Finnish (FIN) AF: 0.234 AC: 2479 AN: 10576

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14455 AN: 68004

Other (OTH) AF: 0.251 AC: 531 AN: 2112

Alfa AF: 0.243 Hom.: 8220

Bravo AF: 0.317

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.214 AC: 825

ESP6500AA AF: 0.403 AC: 1777

ESP6500EA AF: 0.214 AC: 1840

ExAC AF: 0.301 AC: 36519

Asia WGS AF: 0.472 AC: 1640 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.000036	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.95	L
PhyloP100		0.56
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.28
ClinPred		0.0022	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228564; hg19: chr1-40773149; COSMIC: COSV107474543; COSMIC: COSV107474543;