rs2228565

Positions:

chr1-40310265-G-A

Variant summary

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

The NM_001852.4(COL9A2):c.737C>T(p.Thr246Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,614,028 control chromosomes in the GnomAD database, including 1,056 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T246T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.021 ( 61 hom., cov: 32)

Exomes 𝑓: 0.033 ( 995 hom. )

Consequence

COL9A2
NM_001852.4 missense, splice_region

Scores

Splicing: ADA: 0.0001059

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.167

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:

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=0.0078905225).

BP6

Variant 1-40310265-G-A is Benign according to our data. Variant chr1-40310265-G-A is described in ClinVar as [Benign]. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in Lovd as [Benign]. Variant chr1-40310265-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3261/152252) while in subpopulation NFE AF= 0.0339 (2304/67998). AF 95% confidence interval is 0.0327. There are 61 homozygotes in gnomad4. There are 1536 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.737C>T	p.Thr246Met	missense_variant, splice_region_variant	14/32	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL9A2	ENST00000372748.8 linkuse as main transcript	c.737C>T	p.Thr246Met	missense_variant, splice_region_variant	14/32	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1040C>T		splice_region_variant, non_coding_transcript_exon_variant	13/31	1
COL9A2	ENST00000488463.6 linkuse as main transcript	n.788C>T		splice_region_variant, non_coding_transcript_exon_variant	13/14	5
COL9A2	ENST00000417105.6 linkuse as main transcript	c.*25C>T		downstream_gene_variant		5		ENSP00000388493.2	H0Y409

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3262

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0339

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0218

AC:

5493

AN:

251406

Hom.:

AF XY:

0.0219

AC XY:

2977

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00708

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.00675

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00523

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0337

Gnomad OTH exome

AF:

0.0241

GnomAD4 exome

AF:

0.0331

AC:

48426

AN:

1461776

Hom.:

995

Cov.:

AF XY:

0.0323

AC XY:

23512

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.00654

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00538

Gnomad4 FIN exome

AF:

0.0367

Gnomad4 NFE exome

AF:

0.0389

Gnomad4 OTH exome

AF:

0.0308

GnomAD4 genome

AF:

0.0214

AC:

3261

AN:

152252

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1536

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00631

Gnomad4 AMR

AF:

0.0107

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.0388

Gnomad4 NFE

AF:

0.0339

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0295

Hom.:

110

Bravo

AF:

0.0202

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.0345

AC:

297

ExAC

AF:

0.0222

AC:

2694

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0300

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
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	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. -

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

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.18

DANN

Benign

0.60

DEOGEN2

Benign

0.040

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Benign

0.17

Polyphen

0.0020

Vest4

0.17

MPC

0.77

ClinPred

0.014

GERP RS

-9.3

Varity_R

0.026

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.044

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