rs56326652

Variant names:

• chr1-40310254-A-G
• rs56326652
• NM_001852.4:c.738+10T>C

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.738+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,950 control chromosomes in the GnomAD database, including 2,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (217 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2364 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.267
• Publications: 3 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), G2P, Genomics England PanelApp, Ambry Genetics
• 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=-0.84).
• BP6: Variant 1-40310254-A-G is Benign according to our data. Variant chr1-40310254-A-G is described in ClinVar as Benign. ClinVar VariationId is 258394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0631 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.738+10T>C		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.738+10T>C		intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1041+10T>C		intron	N/A
	COL9A2	ENST00000869268.1		c.738+10T>C		intron	N/A	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6481 AN: 152114 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0444 AC: 11170 AN: 251408 AF XY: 0.0458

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0442

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0544 AC: 79587 AN: 1461718 Hom.: 2364 Cov.: 34 AF XY: 0.0542 AC XY: 39403 AN XY: 727172

African (AFR) AF: 0.00848 AC: 284 AN: 33478

American (AMR) AF: 0.0227 AC: 1017 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 1223 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0298 AC: 2571 AN: 86258

European-Finnish (FIN) AF: 0.0660 AC: 3522 AN: 53398

Middle Eastern (MID) AF: 0.0293 AC: 169 AN: 5768

European-Non Finnish (NFE) AF: 0.0611 AC: 67939 AN: 1111864

Other (OTH) AF: 0.0474 AC: 2861 AN: 60394

GnomAD4 genome AF: 0.0426 AC: 6480 AN: 152232 Hom.: 217 Cov.: 32 AF XY: 0.0429 AC XY: 3191 AN XY: 74424

African (AFR) AF: 0.0100 AC: 417 AN: 41524

American (AMR) AF: 0.0290 AC: 443 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 163 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0303 AC: 146 AN: 4826

European-Finnish (FIN) AF: 0.0772 AC: 818 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0647 AC: 4401 AN: 68004

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0486 Hom.: 71

Bravo AF: 0.0365

Asia WGS AF: 0.0130 AC: 46 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	Connective tissue disorder (1)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.64
PhyloP100		-0.27
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56326652;

hg19: chr1-40775926;