1-40307477-T-C

Position:

chr1-40307477-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_001852.4(COL9A2):c.977A>G(p.Gln326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,613,126 control chromosomes in the GnomAD database, including 59,315 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q326W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.30 ( 7863 hom., cov: 32)

Exomes 𝑓: 0.25 ( 51452 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.555

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:

COL9A2 (HGNC:):

COL9A2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=3.5691442E-5).

BP6

Variant 1-40307477-T-C is Benign according to our data. Variant chr1-40307477-T-C is described in ClinVar as [Benign]. Clinvar id is 258399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40307477-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 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.977A>G	p.Gln326Arg	missense_variant	19/32	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8 linkuse as main transcript	c.977A>G	p.Gln326Arg	missense_variant	19/32	1	NM_001852.4	ENSP00000361834.3		Q14055
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1280A>G		non_coding_transcript_exon_variant	18/31	1

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45539

AN:

151986

Hom.:

7827

Cov.:

show subpopulations

Gnomad AFR

AF:

0.408

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.363

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.249

GnomAD3 exomes

AF:

0.304

AC:

76240

AN:

250534

Hom.:

13998

AF XY:

0.290

AC XY:

39333

AN XY:

135490

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.481

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.600

Gnomad SAS exome

AF:

0.292

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.215

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.249

AC:

363223

AN:

1461022

Hom.:

51452

Cov.:

AF XY:

0.248

AC XY:

180398

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.420

Gnomad4 AMR exome

AF:

0.466

Gnomad4 ASJ exome

AF:

0.204

Gnomad4 EAS exome

AF:

0.652

Gnomad4 SAS exome

AF:

0.288

Gnomad4 FIN exome

AF:

0.245

Gnomad4 NFE exome

AF:

0.218

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.300

AC:

45640

AN:

152104

Hom.:

7863

Cov.:

AF XY:

0.303

AC XY:

22540

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.409

Gnomad4 AMR

AF:

0.363

Gnomad4 ASJ

AF:

0.200

Gnomad4 EAS

AF:

0.620

Gnomad4 SAS

AF:

0.305

Gnomad4 FIN

AF:

0.234

Gnomad4 NFE

AF:

0.213

Gnomad4 OTH

AF:

0.251

Alfa

AF:

0.235

Hom.:

5161

Bravo

AF:

0.317

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.214

AC:

825

ESP6500AA

AF:

0.403

AC:

1777

ESP6500EA

AF:

0.214

AC:

1840

ExAC

AF:

0.301

AC:

36519

Asia WGS

AF:

0.472

AC:

1640

AN:

3478

EpiCase

AF:

0.208

EpiControl

AF:

0.200

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.12

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.21

MetaRNN

Benign

0.000036

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.95

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.82

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.042

MPC

0.28

ClinPred

0.0022

GERP RS

5.0

Varity_R

0.12

gMVP

0.22

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

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