rs56326652

Positions:

• chr1-40310254-A-G

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.738+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,950 control chromosomes in the GnomAD database, including 2,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (217 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2364 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.267

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=-0.84).
• BP6: Variant 1-40310254-A-G is Benign according to our data. Variant chr1-40310254-A-G is described in ClinVar as [Benign]. Clinvar id is 258394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310254-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.738+10T>C		intron_variant		ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.738+10T>C		intron_variant		1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.1041+10T>C		intron_variant, non_coding_transcript_variant		1
COL9A2	ENST00000488463.6	n.789+10T>C		intron_variant, non_coding_transcript_variant		5
COL9A2	ENST00000417105.6			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6481 AN: 152114 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0444 AC: 11170 AN: 251408 Hom.: 333 AF XY: 0.0458 AC XY: 6221 AN XY: 135876

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0442

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0544 AC: 79587 AN: 1461718 Hom.: 2364 Cov.: 34 AF XY: 0.0542 AC XY: 39403 AN XY: 727172

Gnomad4 AFR exome AF: 0.00848

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0298

Gnomad4 FIN exome AF: 0.0660

Gnomad4 NFE exome AF: 0.0611

Gnomad4 OTH exome AF: 0.0474

GnomAD4 genome AF: 0.0426 AC: 6480 AN: 152232 Hom.: 217 Cov.: 32 AF XY: 0.0429 AC XY: 3191 AN XY: 74424

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0470

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0303

Gnomad4 FIN AF: 0.0772

Gnomad4 NFE AF: 0.0647

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0486 Hom.: 71

Bravo AF: 0.0365

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs56326652; hg19: chr1-40775926;