rs2229826

Positions:

chr1-40301251-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001852.4(COL9A2):c.2001C>T(p.Ala667Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,132 control chromosomes in the GnomAD database, including 545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 28 hom., cov: 32)

Exomes 𝑓: 0.024 ( 517 hom. )

Consequence

COL9A2
NM_001852.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.65

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 1-40301251-G-A is Benign according to our data. Variant chr1-40301251-G-A is described in ClinVar as [Benign]. Clinvar id is 258383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40301251-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.65 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2631/152316) while in subpopulation NFE AF= 0.024 (1635/68032). AF 95% confidence interval is 0.0231. There are 28 homozygotes in gnomad4. There are 1334 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.2001C>T	p.Ala667Ala	synonymous_variant	32/32	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.2001C>T	p.Ala667Ala	synonymous_variant	32/32	1	NM_001852.4	ENSP00000361834.3		Q14055
COL9A2	ENST00000482722.5 linkuse as main transcript	n.2304C>T		non_coding_transcript_exon_variant	31/31	1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2630

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0177

AC:

4414

AN:

249702

Hom.:

AF XY:

0.0178

AC XY:

2411

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00466

Gnomad AMR exome

AF:

0.00503

Gnomad ASJ exome

AF:

0.00826

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0118

Gnomad FIN exome

AF:

0.0453

Gnomad NFE exome

AF:

0.0233

Gnomad OTH exome

AF:

0.0198

GnomAD4 exome

AF:

0.0240

AC:

35049

AN:

1461816

Hom.:

517

Cov.:

AF XY:

0.0239

AC XY:

17402

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.00561

Gnomad4 ASJ exome

AF:

0.00792

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0124

Gnomad4 FIN exome

AF:

0.0462

Gnomad4 NFE exome

AF:

0.0267

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0173

AC:

2631

AN:

152316

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1334

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00476

Gnomad4 AMR

AF:

0.00856

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00911

Gnomad4 FIN

AF:

0.0513

Gnomad4 NFE

AF:

0.0240

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0135

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0223

EpiControl

AF:

0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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. -

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

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.7

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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