rs3737815

Variant names:

• chr1-40311080-C-A
• rs3737815
• NM_001852.4:c.630+13G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40311080-C-A
• chr1-40311080-C-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.630+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,654 control chromosomes in the GnomAD database, including 24,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1917 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23065 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0370
• Publications: 12 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 (BayesDel_noAF=-0.68).
• BP6: Variant 1-40311080-C-A is Benign according to our data. Variant chr1-40311080-C-A is described in ClinVar as Benign. ClinVar VariationId is 258392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 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.630+13G>T		intron	N/A	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.630+13G>T		intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.933+13G>T		intron	N/A
	COL9A2	ENST00000869268.1		c.630+13G>T		intron	N/A	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21272 AN: 152082 Hom.: 1915 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.0977

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.174 AC: 43816 AN: 251264 AF XY: 0.168

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.168 AC: 245050 AN: 1461454 Hom.: 23065 Cov.: 37 AF XY: 0.166 AC XY: 120408 AN XY: 727042

African (AFR) AF: 0.0497 AC: 1662 AN: 33468

American (AMR) AF: 0.243 AC: 10857 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3583 AN: 26132

East Asian (EAS) AF: 0.431 AC: 17091 AN: 39698

South Asian (SAS) AF: 0.0987 AC: 8508 AN: 86244

European-Finnish (FIN) AF: 0.187 AC: 9969 AN: 53418

Middle Eastern (MID) AF: 0.0818 AC: 456 AN: 5576

European-Non Finnish (NFE) AF: 0.165 AC: 183126 AN: 1111832

Other (OTH) AF: 0.162 AC: 9798 AN: 60366

GnomAD4 genome AF: 0.140 AC: 21274 AN: 152200 Hom.: 1917 Cov.: 32 AF XY: 0.141 AC XY: 10462 AN XY: 74404

African (AFR) AF: 0.0532 AC: 2209 AN: 41552

American (AMR) AF: 0.201 AC: 3074 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 470 AN: 3470

East Asian (EAS) AF: 0.412 AC: 2125 AN: 5152

South Asian (SAS) AF: 0.0971 AC: 468 AN: 4818

European-Finnish (FIN) AF: 0.178 AC: 1882 AN: 10602

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10591 AN: 67986

Other (OTH) AF: 0.121 AC: 255 AN: 2114

Alfa AF: 0.136 Hom.: 955

Bravo AF: 0.141

Asia WGS AF: 0.228 AC: 793 AN: 3478

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
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.7
DANN	Benign	0.86
PhyloP100		-0.037
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs3737815; hg19: chr1-40776752; COSMIC: COSV65607609; COSMIC: COSV65607609;