chr1-40307451-G-C

Position:

chr1-40307451-G-C

Variant summary

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

The NM_001852.4(COL9A2):c.1003C>G(p.Leu335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,598 control chromosomes in the GnomAD database, including 12,060 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. L335I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.098 ( 766 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11294 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.394

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=0.0024698377).

BP6

Variant 1-40307451-G-C is Benign according to our data. Variant chr1-40307451-G-C is described in ClinVar as [Benign]. Clinvar id is 258364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40307451-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.1003C>G	p.Leu335Val	missense_variant	19/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8 linkuse as main transcript	c.1003C>G	p.Leu335Val	missense_variant	19/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1306C>G		non_coding_transcript_exon_variant	18/31	1

Frequencies

GnomAD3 genomes

AF:

0.0984

AC:

14978

AN:

152186

Hom.:

768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0667

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0985

Gnomad ASJ

AF:

0.0541

Gnomad EAS

AF:

0.0993

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0843

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.0979

GnomAD3 exomes

AF:

0.104

AC:

26061

AN:

250194

Hom.:

1440

AF XY:

0.106

AC XY:

14346

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.0651

Gnomad AMR exome

AF:

0.0812

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.124

Gnomad SAS exome

AF:

0.109

Gnomad FIN exome

AF:

0.0842

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.121

AC:

177507

AN:

1461294

Hom.:

11294

Cov.:

AF XY:

0.120

AC XY:

87578

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.0617

Gnomad4 AMR exome

AF:

0.0841

Gnomad4 ASJ exome

AF:

0.0627

Gnomad4 EAS exome

AF:

0.0876

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0849

Gnomad4 NFE exome

AF:

0.131

Gnomad4 OTH exome

AF:

0.113

GnomAD4 genome

AF:

0.0984

AC:

14982

AN:

152304

Hom.:

766

Cov.:

AF XY:

0.0956

AC XY:

7124

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0665

Gnomad4 AMR

AF:

0.0987

Gnomad4 ASJ

AF:

0.0541

Gnomad4 EAS

AF:

0.0991

Gnomad4 SAS

AF:

0.111

Gnomad4 FIN

AF:

0.0843

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.108

Hom.:

775

Bravo

AF:

0.0974

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.139

AC:

536

ESP6500AA

AF:

0.0738

AC:

325

ESP6500EA

AF:

0.113

AC:

974

ExAC

AF:

0.104

AC:

12622

Asia WGS

AF:

0.0980

AC:

342

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 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+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.086

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.079

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.65

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.84

REVEL

Benign

0.24

Sift

Benign

0.050

Sift4G

Benign

0.093

Polyphen

0.82

Vest4

0.12

MPC

0.68

ClinPred

0.015

GERP RS

3.0

Varity_R

0.13

gMVP

0.17

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