chr1-40302811-T-TGGAG

Variant names:

• chr1-40302811-T-TGGAG
• rs3831927
• NM_001852.4:c.1604-6_1604-3dupCTCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.1604-6_1604-3dupCTCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 554,618 control chromosomes in the GnomAD database, including 185 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (53 hom., cov: 31)
  • Exomes 𝑓: 0.034 (132 hom.)
• Consequence: COL9A2 NM_001852.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.54
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 1-40302811-T-TGGAG is Benign according to our data. Variant chr1-40302811-T-TGGAG is described in ClinVar as Benign. ClinVar VariationId is 1167800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0754 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	NM_001852.4	MANE Select	c.1604-6_1604-3dupCTCC		splice_region intron	N/A	NP_001843.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.1604-3_1604-2insCTCC		splice_region intron	N/A	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.1907-3_1907-2insCTCC		splice_region intron	N/A
	COL9A2	ENST00000427563.1	TSL:3	n.360-3_360-2insCTCC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 3614 AN: 125770 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0413

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.0174

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0235

GnomAD2 exomes AF: 0.0298 AC: 4095 AN: 137322 AF XY: 0.0294

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0528

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0335 AC: 14374 AN: 428750 Hom.: 132 Cov.: 36 AF XY: 0.0343 AC XY: 7932 AN XY: 231318

African (AFR) AF: 0.0316 AC: 546 AN: 17276

American (AMR) AF: 0.0534 AC: 1517 AN: 28384

Ashkenazi Jewish (ASJ) AF: 0.0596 AC: 746 AN: 12514

East Asian (EAS) AF: 0.0794 AC: 1016 AN: 12788

South Asian (SAS) AF: 0.0337 AC: 2051 AN: 60892

European-Finnish (FIN) AF: 0.0320 AC: 876 AN: 27394

Middle Eastern (MID) AF: 0.0200 AC: 49 AN: 2452

European-Non Finnish (NFE) AF: 0.0278 AC: 6883 AN: 247534

Other (OTH) AF: 0.0354 AC: 690 AN: 19516

GnomAD4 genome AF: 0.0287 AC: 3617 AN: 125868 Hom.: 53 Cov.: 31 AF XY: 0.0292 AC XY: 1744 AN XY: 59798

African (AFR) AF: 0.0388 AC: 1362 AN: 35142

American (AMR) AF: 0.0297 AC: 368 AN: 12376

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 130 AN: 3148

East Asian (EAS) AF: 0.0279 AC: 98 AN: 3514

South Asian (SAS) AF: 0.0386 AC: 132 AN: 3422

European-Finnish (FIN) AF: 0.0302 AC: 180 AN: 5958

Middle Eastern (MID) AF: 0.0187 AC: 5 AN: 268

European-Non Finnish (NFE) AF: 0.0219 AC: 1301 AN: 59528

Other (OTH) AF: 0.0233 AC: 41 AN: 1762

Alfa AF: 0.0182 Hom.: 6

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Epiphyseal dysplasia, multiple, 2;C3280342:Stickler syndrome, type 5 Benign:1

Sep 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Connective tissue disorder Benign:1

Feb 12, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3831927; hg19: chr1-40768483; COSMIC: COSV65622400;