rs11207843

chr1-40312120-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001852.4(COL9A2):c.364-8C>T 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 0.0114 in 1,598,620 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (118 hom., cov: 31)
  • Exomes 𝑓: 0.010 (547 hom.)
• Consequence: COL9A2 NM_001852.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005146
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.463

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-40312120-G-A is Benign according to our data. Variant chr1-40312120-G-A is described in ClinVar as [Benign]. Clinvar id is 258389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40312120-G-A is described in Lovd as [Benign]. Variant chr1-40312120-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.364-8C>T		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.364-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	P1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3774 AN: 152086 Hom.: 116 Cov.: 31

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0295 AC: 6552 AN: 221800 Hom.: 269 AF XY: 0.0260 AC XY: 3096 AN XY: 119100

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.0973

Gnomad ASJ exome AF: 0.000963

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.0326

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.00998 AC: 14430 AN: 1446420 Hom.: 547 Cov.: 32 AF XY: 0.0101 AC XY: 7259 AN XY: 717892

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.0918

Gnomad4 ASJ exome AF: 0.00125

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.000707

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0249 AC: 3789 AN: 152200 Hom.: 118 Cov.: 31 AF XY: 0.0264 AC XY: 1967 AN XY: 74408

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.0609

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0990

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0103 Hom.: 24

Bravo AF: 0.0307

Asia WGS AF: 0.0580 AC: 203 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Epiphyseal dysplasia, multiple, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.9
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11207843; hg19: chr1-40777792;