chr1-40301060-A-G

Variant names:

• chr1-40301060-A-G
• rs2229827
• NM_001852.4:c.*122T>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.*122T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,012,266 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (453 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (323 hom.)
• Consequence: COL9A2 NM_001852.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.254
• 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: Labcorp Genetics (formerly Invitae), G2P
• Stickler syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P, PanelApp Australia
• 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=-0.89).
• BP6: Variant 1-40301060-A-G is Benign according to our data. Variant chr1-40301060-A-G is described in ClinVar as Benign. ClinVar VariationId is 297288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 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.*122T>C		3_prime_UTR	Exon 32 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.*122T>C		3_prime_UTR	Exon 32 of 32	ENSP00000361834.3	Q14055
	COL9A2	ENST00000482722.5	TSL:1	n.2495T>C		non_coding_transcript_exon	Exon 31 of 31
	COL9A2	ENST00000869268.1		c.*122T>C		3_prime_UTR	Exon 32 of 32	ENSP00000539327.1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6438 AN: 152066 Hom.: 446 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.00486 AC: 4182 AN: 860082 Hom.: 323 Cov.: 12 AF XY: 0.00416 AC XY: 1827 AN XY: 439090

African (AFR) AF: 0.157 AC: 3286 AN: 20914

American (AMR) AF: 0.00848 AC: 267 AN: 31484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20504

East Asian (EAS) AF: 0.000149 AC: 5 AN: 33568

South Asian (SAS) AF: 0.000784 AC: 52 AN: 66308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48262

Middle Eastern (MID) AF: 0.00375 AC: 11 AN: 2930

European-Non Finnish (NFE) AF: 0.000146 AC: 87 AN: 596302

Other (OTH) AF: 0.0119 AC: 474 AN: 39810

GnomAD4 genome AF: 0.0425 AC: 6474 AN: 152184 Hom.: 453 Cov.: 32 AF XY: 0.0421 AC XY: 3134 AN XY: 74406

African (AFR) AF: 0.148 AC: 6153 AN: 41512

American (AMR) AF: 0.0153 AC: 234 AN: 15290

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

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68004

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0232 Hom.: 74

Bravo AF: 0.0487

Asia WGS AF: 0.0350 AC: 121 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.61
PhyloP100		-0.25
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

Other links and lift over

dbSNP: rs2229827; hg19: chr1-40766732;