rs118135975

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001852.4(COL9A2):c.955-4C>G 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 0.0206 in 1,613,626 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 45 hom., cov: 32)

Exomes 𝑓: 0.021 ( 421 hom. )

Consequence

COL9A2
NM_001852.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004741

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.131

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 1-40307503-G-C is Benign according to our data. Variant chr1-40307503-G-C is described in ClinVar as [Benign]. Clinvar id is 258397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40307503-G-C is described in Lovd as [Benign]. Variant chr1-40307503-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0176 (2677/152320) while in subpopulation SAS AF= 0.033 (159/4822). AF 95% confidence interval is 0.0288. There are 45 homozygotes in gnomad4. There are 1380 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.955-4C>G		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 linkuse as main transcript	c.955-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	P1
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1258-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2677

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.0256

Gnomad SAS

AF:

0.0329

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0271

AC:

6808

AN:

251116

Hom.:

139

AF XY:

0.0266

AC XY:

3609

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.0530

Gnomad ASJ exome

AF:

0.0413

Gnomad EAS exome

AF:

0.0223

Gnomad SAS exome

AF:

0.0357

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0209

AC:

30498

AN:

1461306

Hom.:

421

Cov.:

AF XY:

0.0216

AC XY:

15666

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.0489

Gnomad4 ASJ exome

AF:

0.0410

Gnomad4 EAS exome

AF:

0.0329

Gnomad4 SAS exome

AF:

0.0349

Gnomad4 FIN exome

AF:

0.0250

Gnomad4 NFE exome

AF:

0.0182

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0176

AC:

2677

AN:

152320

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1380

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00332

Gnomad4 AMR

AF:

0.0250

Gnomad4 ASJ

AF:

0.0406

Gnomad4 EAS

AF:

0.0257

Gnomad4 SAS

AF:

0.0330

Gnomad4 FIN

AF:

0.0230

Gnomad4 NFE

AF:

0.0212

Gnomad4 OTH

AF:

0.0165

Alfa

AF:

0.0238

Hom.:

Bravo

AF:

0.0166

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.0198

EpiControl

AF:

0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Dec 30, 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. -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2019	- -

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

Feb 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

Cadd

Benign

7.3

Dann

Benign

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

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