1-40302811-TGGAGGGAGGGAG-TGGAGGGAGGGAGGGAGGGAG

Variant names:

• chr1-40302811-T-TGGAGGGAG
• rs3831927
• NM_001852.4:c.1604-10_1604-3dupCTCCCTCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001852.4(COL9A2):​c.1604-10_1604-3dupCTCCCTCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 125,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000032 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000070 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL9A2 NM_001852.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-40302811-T-TGGAGGGAG is Benign according to our data. Variant chr1-40302811-T-TGGAGGGAG is described in ClinVar as Likely_benign. ClinVar VariationId is 1146972.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1604-10_1604-3dupCTCCCTCC		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_1604-2insCTCCCTCC		splice_region intron	N/A	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.1907-3_1907-2insCTCCCTCC		splice_region intron	N/A
	COL9A2	ENST00000427563.1	TSL:3	n.360-3_360-2insCTCCCTCC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000318 AC: 4 AN: 125864 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000292

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000168

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000146 AC: 20 AN: 137322 AF XY: 0.000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000761

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000995

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.000253

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000699 AC: 30 AN: 429090 Hom.: 0 Cov.: 36 AF XY: 0.0000605 AC XY: 14 AN XY: 231506

African (AFR) AF: 0.0000575 AC: 1 AN: 17384

American (AMR) AF: 0.000669 AC: 19 AN: 28414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12526

East Asian (EAS) AF: 0.000234 AC: 3 AN: 12810

South Asian (SAS) AF: 0.00 AC: 0 AN: 60904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2454

European-Non Finnish (NFE) AF: 0.0000162 AC: 4 AN: 247660

Other (OTH) AF: 0.000154 AC: 3 AN: 19534

GnomAD4 genome AF: 0.0000318 AC: 4 AN: 125864 Hom.: 0 Cov.: 31 AF XY: 0.0000167 AC XY: 1 AN XY: 59778

African (AFR) AF: 0.00 AC: 0 AN: 35094

American (AMR) AF: 0.000162 AC: 2 AN: 12370

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3514

South Asian (SAS) AF: 0.000292 AC: 1 AN: 3428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000168 AC: 1 AN: 59558

Other (OTH) AF: 0.00 AC: 0 AN: 1748

Alfa AF: 0.00 Hom.: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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

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;