rs113549021

Variant summary

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

The NM_001852.4(COL9A2):c.544A>G(p.Met182Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,614,144 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 14 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.45

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 (MetaRNN=0.004476011).

BP6

Variant 1-40311262-T-C is Benign according to our data. Variant chr1-40311262-T-C is described in ClinVar as [Benign]. Clinvar id is 258391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40311262-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.008 (1219/152304) while in subpopulation AFR AF= 0.0283 (1177/41556). AF 95% confidence interval is 0.027. There are 13 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	11/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL9A2	ENST00000372748.8 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	11/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5 linkuse as main transcript	n.847A>G		non_coding_transcript_exon_variant	10/31	1
COL9A2	ENST00000417105.6 linkuse as main transcript	c.262A>G	p.Met88Val	missense_variant	11/14	5
COL9A2	ENST00000488463.6 linkuse as main transcript	n.595A>G		non_coding_transcript_exon_variant	10/14	5

Frequencies

GnomAD3 genomes

AF:

0.00799

AC:

1216

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00195

AC:

490

AN:

251220

Hom.:

AF XY:

0.00135

AC XY:

183

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.0277

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000746

AC:

1091

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

463

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0275

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.00800

AC:

1219

AN:

152304

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

574

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0283

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00874

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00254

AC:

308

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2017	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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 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

Jun 18, 2021

- -

COL9A2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

Cadd

Benign

6.7

Dann

Benign

0.68

DEOGEN2

Benign

0.089

T;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.030

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.24

N;.

REVEL

Benign

0.18

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;.

Vest4

0.20

MVP

0.83

MPC

0.26

ClinPred

0.0021

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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