rs2228567

Variant names:

• chr1-40307451-G-C
• rs2228567
• NM_001852.4:c.1003C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-40307451-G-C
• chr1-40307451-G-T
• chr1-40307451-G-A

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.1003C>G​(p.Leu335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,598 control chromosomes in the GnomAD database, including 12,060 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. L335I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (766 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11294 hom.)
• Consequence: COL9A2 NM_001852.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.394
• Publications: 28 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=0.0024698377).
• BP6: Variant 1-40307451-G-C is Benign according to our data. Variant chr1-40307451-G-C is described in ClinVar as Benign. ClinVar VariationId is 258364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 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.1003C>G	p.Leu335Val	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.1003C>G	p.Leu335Val	missense	Exon 19 of 32	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1306C>G		non_coding_transcript_exon	Exon 18 of 31
	COL9A2	ENST00000869268.1		c.1003C>G	p.Leu335Val	missense	Exon 19 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0984 AC: 14978 AN: 152186 Hom.: 768 Cov.: 32

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0985

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0993

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0979

GnomAD2 exomes AF: 0.104 AC: 26061 AN: 250194 AF XY: 0.106

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.0812

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.0842

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.121 AC: 177507 AN: 1461294 Hom.: 11294 Cov.: 32 AF XY: 0.120 AC XY: 87578 AN XY: 726898

African (AFR) AF: 0.0617 AC: 2067 AN: 33478

American (AMR) AF: 0.0841 AC: 3757 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1638 AN: 26128

East Asian (EAS) AF: 0.0876 AC: 3477 AN: 39692

South Asian (SAS) AF: 0.112 AC: 9645 AN: 86186

European-Finnish (FIN) AF: 0.0849 AC: 4531 AN: 53386

Middle Eastern (MID) AF: 0.0640 AC: 369 AN: 5768

European-Non Finnish (NFE) AF: 0.131 AC: 145221 AN: 1111660

Other (OTH) AF: 0.113 AC: 6802 AN: 60342

GnomAD4 genome AF: 0.0984 AC: 14982 AN: 152304 Hom.: 766 Cov.: 32 AF XY: 0.0956 AC XY: 7124 AN XY: 74480

African (AFR) AF: 0.0665 AC: 2764 AN: 41562

American (AMR) AF: 0.0987 AC: 1511 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0991 AC: 514 AN: 5186

South Asian (SAS) AF: 0.111 AC: 538 AN: 4832

European-Finnish (FIN) AF: 0.0843 AC: 895 AN: 10612

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8227 AN: 68014

Other (OTH) AF: 0.101 AC: 213 AN: 2116

Alfa AF: 0.108 Hom.: 775

Bravo AF: 0.0974

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.139 AC: 536

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.113 AC: 974

ExAC AF: 0.104 AC: 12622

Asia WGS AF: 0.0980 AC: 342 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.39
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.24
Sift	Benign	0.050	D
Sift4G	Benign	0.093	T
Polyphen		0.82	P
Vest4		0.12
MPC		0.68
ClinPred		0.015	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.17
Mutation Taster		=99/1	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: rs2228567; hg19: chr1-40773123; COSMIC: COSV65607113; COSMIC: COSV65607113;