1-40312128-T-C

Position:

chr1-40312128-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001852.4(COL9A2):c.364-16A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,595,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

COL9A2
NM_001852.4 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.550

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-40312128-T-C is Benign according to our data. Variant chr1-40312128-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445655.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr1-40312128-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000515 (78/151430) while in subpopulation NFE AF= 0.000928 (63/67876). AF 95% confidence interval is 0.000744. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 31. 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.364-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8 linkuse as main transcript	c.364-16A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000515

AC:

AN:

151430

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000928

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000507

AC:

112

AN:

220972

Hom.:

AF XY:

0.000531

AC XY:

AN XY:

118632

show subpopulations

Gnomad AFR exome

AF:

0.000142

Gnomad AMR exome

AF:

0.000169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000264

Gnomad NFE exome

AF:

0.000982

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.000492

AC:

711

AN:

1444272

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

369

AN XY:

716720

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.000198

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000191

Gnomad4 NFE exome

AF:

0.000607

Gnomad4 OTH exome

AF:

0.000301

GnomAD4 genome

AF:

0.000515

AC:

AN:

151430

Hom.:

Cov.:

AF XY:

0.000582

AC XY:

AN XY:

73892

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.000394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000953

Gnomad4 NFE

AF:

0.000928

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000135

Hom.:

410

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2023	Variant summary: COL9A2 c.364-16A>G alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00051 in 220972 control chromosomes. To our knowledge, no occurrence of c.364-16A>G in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

COL9A2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.1

DANN

Benign

0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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