1-40312132-T-C

Variant names:

• chr1-40312132-T-C
• rs78091688
• ENST00000482722.5:n.647A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000482722.5(COL9A2):​n.647A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,592,960 control chromosomes in the GnomAD database, including 3,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (944 hom., cov: 31)
  • Exomes 𝑓: 0.039 (2249 hom.)
• Consequence: COL9A2 ENST00000482722.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.23
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 1-40312132-T-C is Benign according to our data. Variant chr1-40312132-T-C is described in ClinVar as Benign. ClinVar VariationId is 258388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000482722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	NM_001852.4	MANE Select	c.364-20A>G		intron	N/A	NP_001843.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000482722.5	TSL:1	n.647A>G		non_coding_transcript_exon	Exon 7 of 31
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.364-20A>G		intron	N/A	ENSP00000361834.3
	COL9A2	ENST00000417105.6	TSL:5	c.82-20A>G		intron	N/A	ENSP00000388493.2

Frequencies

GnomAD3 genomes AF: 0.0835 AC: 12638 AN: 151398 Hom.: 932 Cov.: 31

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0639

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0988

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0602

GnomAD2 exomes AF: 0.0602 AC: 13309 AN: 221050 AF XY: 0.0570

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0681

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0442

GnomAD4 exome AF: 0.0387 AC: 55851 AN: 1441470 Hom.: 2249 Cov.: 32 AF XY: 0.0390 AC XY: 27919 AN XY: 715410

African (AFR) AF: 0.208 AC: 6895 AN: 33212

American (AMR) AF: 0.0669 AC: 2698 AN: 40308

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 470 AN: 25608

East Asian (EAS) AF: 0.152 AC: 5942 AN: 39040

South Asian (SAS) AF: 0.0797 AC: 6584 AN: 82564

European-Finnish (FIN) AF: 0.0260 AC: 1366 AN: 52476

Middle Eastern (MID) AF: 0.0477 AC: 273 AN: 5724

European-Non Finnish (NFE) AF: 0.0260 AC: 28718 AN: 1102818

Other (OTH) AF: 0.0486 AC: 2905 AN: 59720

GnomAD4 genome AF: 0.0837 AC: 12676 AN: 151490 Hom.: 944 Cov.: 31 AF XY: 0.0850 AC XY: 6289 AN XY: 73994

African (AFR) AF: 0.194 AC: 7997 AN: 41156

American (AMR) AF: 0.0614 AC: 937 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3464

East Asian (EAS) AF: 0.166 AC: 854 AN: 5136

South Asian (SAS) AF: 0.0992 AC: 475 AN: 4786

European-Finnish (FIN) AF: 0.0276 AC: 289 AN: 10480

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1855 AN: 67916

Other (OTH) AF: 0.0610 AC: 128 AN: 2100

Alfa AF: 0.0555 Hom.: 176

Bravo AF: 0.0910

Asia WGS AF: 0.135 AC: 469 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.7
DANN	Benign	0.36
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78091688; hg19: chr1-40777804;