chr1-40312120-G-A

Position:

chr1-40312120-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000372748.8(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
ENST00000372748.8 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005146

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.463

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.364-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8 linkuse as main transcript	c.364-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	ENSP00000361834	P1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3774

AN:

152086

Hom.:

116

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0101

AC XY:

7259

AN XY:

717892

show subpopulations

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.:

AF XY:

0.0264

AC XY:

1967

AN XY:

74408

show subpopulations

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.:

Bravo

AF:

0.0307

Asia WGS

AF:

0.0580

AC:

203

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over