1-40307478-G-A

Position:

chr1-40307478-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_001852.4(COL9A2):c.976C>T(p.Gln326Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,614,022 control chromosomes in the GnomAD database, including 939 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.040 ( 276 hom., cov: 32)

Exomes 𝑓: 0.011 ( 663 hom. )

Consequence

COL9A2
NM_001852.4 stop_gained

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.07

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 1-40307478-G-A is Benign according to our data. Variant chr1-40307478-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40307478-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 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.976C>T	p.Gln326Ter	stop_gained	19/32	ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8 linkuse as main transcript	c.976C>T	p.Gln326Ter	stop_gained	19/32	1	NM_001852.4	ENSP00000361834	P1
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1279C>T		non_coding_transcript_exon_variant	18/31	1

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6075

AN:

152158

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0443

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0368

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.0363

GnomAD3 exomes

AF:

0.0312

AC:

7822

AN:

250928

Hom.:

316

AF XY:

0.0273

AC XY:

3706

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0698

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.113

Gnomad SAS exome

AF:

0.0334

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.00216

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0115

AC:

16809

AN:

1461746

Hom.:

663

Cov.:

AF XY:

0.0115

AC XY:

8352

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.110

Gnomad4 AMR exome

AF:

0.0652

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.116

Gnomad4 SAS exome

AF:

0.0314

Gnomad4 FIN exome

AF:

0.0123

Gnomad4 NFE exome

AF:

0.000939

Gnomad4 OTH exome

AF:

0.0186

GnomAD4 genome

AF:

0.0400

AC:

6085

AN:

152276

Hom.:

276

Cov.:

AF XY:

0.0399

AC XY:

2969

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.0445

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.109

Gnomad4 SAS

AF:

0.0369

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.0364

Alfa

AF:

0.0110

Hom.:

129

Bravo

AF:

0.0465

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0906

AC:

399

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0317

AC:

3849

Asia WGS

AF:

0.0610

AC:

215

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Epiphyseal dysplasia, multiple, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.83

MutationTaster

Benign

2.0e-19

Vest4

0.74

GERP RS

3.9

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