1-40304805-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001852.4(COL9A2):c.1150A>C(p.Met384Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,550,918 control chromosomes in the GnomAD database, including 22 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0070 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 13 hom. )

Consequence

COL9A2
NM_001852.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.228

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001852.4

BP4

Computational evidence support a benign effect (MetaRNN=0.00675714).

BP6

Variant 1-40304805-T-G is Benign according to our data. Variant chr1-40304805-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 258366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40304805-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00699 (1064/152292) while in subpopulation AFR AF= 0.0233 (967/41576). AF 95% confidence interval is 0.022. There are 9 homozygotes in gnomad4. There are 501 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A2	NM_001852.4 link	c.1150A>C	p.Met384Leu	missense_variant	Exon 22 of 32	ENST00000372748.8	NP_001843.1	Q14055

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL9A2	ENST00000372748.8 link	c.1150A>C	p.Met384Leu	missense_variant	Exon 22 of 32	1	NM_001852.4	ENSP00000361834.3	Q14055
COL9A2	ENST00000482722.5 link	n.1453A>C		non_coding_transcript_exon_variant	Exon 21 of 31	1
COL9A2	ENST00000466267.1 link	n.115A>C		non_coding_transcript_exon_variant	Exon 2 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.00700

AC:

1065

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00174

AC:

271

AN:

155948

Hom.:

AF XY:

0.00122

AC XY:

100

AN XY:

82044

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000825

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.000699

AC:

977

AN:

1398626

Hom.:

Cov.:

AF XY:

0.000583

AC XY:

402

AN XY:

689878

show subpopulations

Gnomad4 AFR exome

AF:

0.0237

Gnomad4 AMR exome

AF:

0.00182

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.00153

GnomAD4 genome

AF:

0.00699

AC:

1064

AN:

152292

Hom.:

Cov.:

AF XY:

0.00673

AC XY:

501

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0233

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.000887

Hom.:

Bravo

AF:

0.00771

ESP6500AA

AF:

0.0206

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00118

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Connective tissue disorder

Benign:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

2.5

DANN

Benign

0.74

DEOGEN2

Benign

0.019

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.91

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.68

REVEL

Benign

0.23

Sift

Benign

0.32

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.17

MutPred

0.45

Loss of MoRF binding (P = 0.1389);

MVP

0.55

MPC

0.26

ClinPred

0.0018

GERP RS

-5.8

Varity_R

0.098

gMVP

0.12

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