1-40302811-TGGAGGGAGGGAG-TGGAGGGAGGGAGGGAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001852.4(COL9A2):c.1604-3_1604-2insCTCC variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.54

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.1604-3_1604-2insCTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.1604-3_1604-2insCTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.1907-3_1907-2insCTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
COL9A2	ENST00000427563.1	n.360-3_360-2insCTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3
COL9A2	ENST00000466267.1	n.569-3_569-2insCTCC		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.0298 AC: 4095 AN: 137322 Hom.: 42 AF XY: 0.0294 AC XY: 2185 AN XY: 74414

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 SAS exome AF: 0.0366

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

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.0534

Gnomad4 ASJ exome AF: 0.0596

Gnomad4 EAS exome AF: 0.0794

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0354

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

Gnomad4 AFR AF: 0.0388

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0413

Gnomad4 EAS AF: 0.0279

Gnomad4 SAS AF: 0.0386

Gnomad4 FIN AF: 0.0302

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0233

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3831927; hg19: chr1-40768483;