1-40314169-G-T

Variant names:

• chr1-40314169-G-T
• rs2273195
• NM_001852.4:c.249+36C>A

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.249+36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 1,610,956 control chromosomes in the GnomAD database, including 5,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1239 hom., cov: 32)
  • Exomes 𝑓: 0.063 (4202 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20
• Publications: 4 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=-0.83).
• BP6: Variant 1-40314169-G-T is Benign according to our data. Variant chr1-40314169-G-T is described in ClinVar as Benign. ClinVar VariationId is 258384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 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.249+36C>A		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.249+36C>A		intron	N/A	ENSP00000361834.3	Q14055
	COL9A2	ENST00000461118.6	TSL:1	n.815+36C>A		intron	N/A
	COL9A2	ENST00000482722.5	TSL:1	n.209+36C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16136 AN: 152020 Hom.: 1227 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0800

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0506

Gnomad OTH AF: 0.0819

GnomAD2 exomes AF: 0.0879 AC: 22101 AN: 251302 AF XY: 0.0858

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0923

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.0427

Gnomad NFE exome AF: 0.0492

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.0625 AC: 91204 AN: 1458818 Hom.: 4202 Cov.: 32 AF XY: 0.0641 AC XY: 46524 AN XY: 725900

African (AFR) AF: 0.227 AC: 7568 AN: 33408

American (AMR) AF: 0.0905 AC: 4047 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 1671 AN: 26118

East Asian (EAS) AF: 0.181 AC: 7196 AN: 39680

South Asian (SAS) AF: 0.131 AC: 11319 AN: 86176

European-Finnish (FIN) AF: 0.0420 AC: 2243 AN: 53376

Middle Eastern (MID) AF: 0.0861 AC: 475 AN: 5516

European-Non Finnish (NFE) AF: 0.0471 AC: 52273 AN: 1109552

Other (OTH) AF: 0.0732 AC: 4412 AN: 60270

GnomAD4 genome AF: 0.106 AC: 16172 AN: 152138 Hom.: 1239 Cov.: 32 AF XY: 0.108 AC XY: 8036 AN XY: 74406

African (AFR) AF: 0.214 AC: 8890 AN: 41480

American (AMR) AF: 0.0800 AC: 1223 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.189 AC: 974 AN: 5160

South Asian (SAS) AF: 0.152 AC: 733 AN: 4828

European-Finnish (FIN) AF: 0.0406 AC: 430 AN: 10598

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0506 AC: 3440 AN: 67996

Other (OTH) AF: 0.0820 AC: 173 AN: 2110

Alfa AF: 0.0715 Hom.: 2369

Bravo AF: 0.112

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.49
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2273195; hg19: chr1-40779841; COSMIC: COSV65607270; COSMIC: COSV65607270;