NM_001852.4:c.364-8C>T

Variant names:

• chr1-40312120-G-A
• rs11207843
• NM_001852.4:c.364-8C>T

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.364-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,598,620 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (118 hom., cov: 31)
  • Exomes 𝑓: 0.010 (547 hom.)
• Consequence: COL9A2 NM_001852.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005146
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.463
• Publications: 5 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=-0.82).
• BP6: Variant 1-40312120-G-A is Benign according to our data. Variant chr1-40312120-G-A is described in ClinVar as Benign. ClinVar VariationId is 258389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0919 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.364-8C>T		splice_region 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.364-8C>T		splice_region intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.659C>T		non_coding_transcript_exon	Exon 7 of 31
	COL9A2	ENST00000869268.1		c.364-8C>T		splice_region intron	N/A	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3774 AN: 152086 Hom.: 116 Cov.: 31

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0295 AC: 6552 AN: 221800 AF XY: 0.0260

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.0973

Gnomad ASJ exome AF: 0.000963

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.00998 AC: 14430 AN: 1446420 Hom.: 547 Cov.: 32 AF XY: 0.0101 AC XY: 7259 AN XY: 717892

African (AFR) AF: 0.0461 AC: 1538 AN: 33382

American (AMR) AF: 0.0918 AC: 3737 AN: 40694

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 32 AN: 25660

East Asian (EAS) AF: 0.108 AC: 4242 AN: 39144

South Asian (SAS) AF: 0.0301 AC: 2491 AN: 82788

European-Finnish (FIN) AF: 0.0124 AC: 650 AN: 52600

Middle Eastern (MID) AF: 0.00698 AC: 40 AN: 5732

European-Non Finnish (NFE) AF: 0.000707 AC: 782 AN: 1106464

Other (OTH) AF: 0.0153 AC: 918 AN: 59956

GnomAD4 genome AF: 0.0249 AC: 3789 AN: 152200 Hom.: 118 Cov.: 31 AF XY: 0.0264 AC XY: 1967 AN XY: 74408

African (AFR) AF: 0.0461 AC: 1914 AN: 41522

American (AMR) AF: 0.0609 AC: 931 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.0990 AC: 511 AN: 5160

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4820

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68024

Other (OTH) AF: 0.0246 AC: 52 AN: 2112

Alfa AF: 0.0111 Hom.: 36

Bravo AF: 0.0307

Asia WGS AF: 0.0580 AC: 203 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Epiphyseal dysplasia, multiple, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.46
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0060
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: rs11207843; hg19: chr1-40777792; COSMIC: COSV101025631; COSMIC: COSV101025631;