1-40302811-TGGAGGGAGGGAG-TGGAGGGAG

Position:

chr1-40302811-TGGAGGGAGGGAG-TGGAGGGAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP6_Very_StrongBS1

The NM_001852.4(COL9A2):c.1604-6_1604-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 524,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0046 ( 0 hom. )

Consequence

COL9A2
NM_001852.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.54

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 -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 1-40302811-TGGAG-T is Benign according to our data. Variant chr1-40302811-TGGAG-T is described in ClinVar as [Likely_benign]. Clinvar id is 777748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40302811-TGGAG-T is described in Lovd as [Benign]. Variant chr1-40302811-TGGAG-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000357 (45/125902) while in subpopulation AMR AF= 0.00145 (18/12390). AF 95% confidence interval is 0.000938. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4 linkuse as main transcript	c.1604-6_1604-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
COL9A2	ENST00000372748.8 linkuse as main transcript	c.1604-6_1604-3del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_001852.4	P1
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1907-6_1907-3del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	1
COL9A2	ENST00000427563.1 linkuse as main transcript	n.360-6_360-3del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	3
COL9A2	ENST00000466267.1 linkuse as main transcript	n.569-6_569-3del	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.000366

AC:

AN:

125804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000399

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00146

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000569

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000337

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000101

Gnomad OTH

AF:

0.00229

GnomAD4 exome

AF:

0.00456

AC:

1816

AN:

398560

Hom.:

AF XY:

0.00424

AC XY:

913

AN XY:

215180

show subpopulations

Gnomad4 AFR exome

AF:

0.00214

Gnomad4 AMR exome

AF:

0.00126

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.00626

Gnomad4 SAS exome

AF:

0.000922

Gnomad4 FIN exome

AF:

0.00280

Gnomad4 NFE exome

AF:

0.00636

Gnomad4 OTH exome

AF:

0.00421

GnomAD4 genome

AF:

0.000357

AC:

AN:

125902

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

AN XY:

59824

show subpopulations

Gnomad4 AFR

AF:

0.000370

Gnomad4 AMR

AF:

0.00145

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000569

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000337

Gnomad4 NFE

AF:

0.000101

Gnomad4 OTH

AF:

0.00227

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

COL9A2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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