chr1-40304046-A-C

Variant names:

• chr1-40304046-A-C
• rs186166446
• NM_001852.4:c.1323+18T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001852.4(COL9A2):​c.1323+18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,578,890 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.575
• Publications: 0 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=-0.9).
• BP6: Variant 1-40304046-A-C is Benign according to our data. Variant chr1-40304046-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0034 (518/152166) while in subpopulation AFR AF = 0.0119 (496/41522). AF 95% confidence interval is 0.0111. There are 3 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.1323+18T>G		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.1323+18T>G		intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.1626+18T>G		intron	N/A
	COL9A2	ENST00000869268.1		c.1407+18T>G		intron	N/A	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 517 AN: 152048 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000677 AC: 129 AN: 190470 AF XY: 0.000479

Gnomad AFR exome AF: 0.00975

Gnomad AMR exome AF: 0.000542

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000204

GnomAD4 exome AF: 0.000289 AC: 412 AN: 1426724 Hom.: 3 Cov.: 33 AF XY: 0.000277 AC XY: 196 AN XY: 706308

African (AFR) AF: 0.00995 AC: 329 AN: 33062

American (AMR) AF: 0.000854 AC: 33 AN: 38658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 38322

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49914

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5678

European-Non Finnish (NFE) AF: 0.00000639 AC: 7 AN: 1095152

Other (OTH) AF: 0.000660 AC: 39 AN: 59068

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152166 Hom.: 3 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74408

African (AFR) AF: 0.0119 AC: 496 AN: 41522

American (AMR) AF: 0.00105 AC: 16 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67972

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epiphyseal dysplasia, multiple, 2;C3280342:Stickler syndrome, type 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.63
DANN	Benign	0.32
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186166446; hg19: chr1-40769718;