1-40302811-TGGAGGGAGGGAG-TGGAGGGAG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_001852.4(COL9A2):​c.1604-6_1604-3delCTCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 524,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0046 (0 hom.)
• Consequence: COL9A2 NM_001852.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -12 ACMG points.

• BP6: Variant 1-40302811-TGGAG-T is Benign according to our data. Variant chr1-40302811-TGGAG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 777748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000357 (45/125902) while in subpopulation AMR AF = 0.00145 (18/12390). AF 95% confidence interval is 0.000938. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

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_1604-3delCTCC		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.1604-6_1604-3delCTCC		splice_region intron	N/A	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.1907-6_1907-3delCTCC		splice_region intron	N/A
	COL9A2	ENST00000427563.1	TSL:3	n.360-6_360-3delCTCC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000366 AC: 46 AN: 125804 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000569

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000337

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000101

Gnomad OTH AF: 0.00229

GnomAD2 exomes AF: 0.000408 AC: 56 AN: 137322 AF XY: 0.000376

Gnomad AFR exome AF: 0.000294

Gnomad AMR exome AF: 0.000358

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000497

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.000758

GnomAD4 exome AF: 0.00456 AC: 1816 AN: 398560 Hom.: 0 AF XY: 0.00424 AC XY: 913 AN XY: 215180

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00214 AC: 36 AN: 16788

American (AMR) AF: 0.00126 AC: 34 AN: 26986

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 24 AN: 11606

East Asian (EAS) AF: 0.00626 AC: 69 AN: 11018

South Asian (SAS) AF: 0.000922 AC: 54 AN: 58590

European-Finnish (FIN) AF: 0.00280 AC: 72 AN: 25672

Middle Eastern (MID) AF: 0.00173 AC: 4 AN: 2310

European-Non Finnish (NFE) AF: 0.00636 AC: 1448 AN: 227786

Other (OTH) AF: 0.00421 AC: 75 AN: 17804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000357 AC: 45 AN: 125902 Hom.: 0 Cov.: 30 AF XY: 0.000401 AC XY: 24 AN XY: 59824

African (AFR) AF: 0.000370 AC: 13 AN: 35172

American (AMR) AF: 0.00145 AC: 18 AN: 12390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3148

East Asian (EAS) AF: 0.000569 AC: 2 AN: 3514

South Asian (SAS) AF: 0.00 AC: 0 AN: 3424

European-Finnish (FIN) AF: 0.000337 AC: 2 AN: 5942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000101 AC: 6 AN: 59534

Other (OTH) AF: 0.00227 AC: 4 AN: 1760

Alfa AF: 0.00386 Hom.: 6

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL9A2-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3831927; hg19: chr1-40768483; COSMIC: COSV107474832;