rs77695700

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001852.4(COL9A2):c.1288-12C>T 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 0.0332 in 1,548,576 control chromosomes in the GnomAD database, including 1,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 136 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1287 hom. )

Consequence

COL9A2
NM_001852.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001605

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.35

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-40304111-G-A is Benign according to our data. Variant chr1-40304111-G-A is described in ClinVar as [Benign]. Clinvar id is 258370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40304111-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 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.1288-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
COL9A2	ENST00000372748.8 linkuse as main transcript	c.1288-12C>T	splice_polypyrimidine_tract_variant, intron_variant	1	NM_001852.4	ENSP00000361834	P1
COL9A2	ENST00000482722.5 linkuse as main transcript	n.1591-12C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	1
COL9A2	ENST00000427563.1 linkuse as main transcript	n.99-12C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	3
COL9A2	ENST00000466267.1 linkuse as main transcript	n.253-12C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4529

AN:

152082

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00782

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.0966

Gnomad FIN

AF:

0.0273

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0259

GnomAD3 exomes

AF:

0.0515

AC:

8017

AN:

155602

Hom.:

363

AF XY:

0.0524

AC XY:

4367

AN XY:

83346

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0562

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.0825

Gnomad FIN exome

AF:

0.0296

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0382

GnomAD4 exome

AF:

0.0336

AC:

46945

AN:

1396376

Hom.:

1287

Cov.:

AF XY:

0.0348

AC XY:

23939

AN XY:

688640

show subpopulations

Gnomad4 AFR exome

AF:

0.00723

Gnomad4 AMR exome

AF:

0.0531

Gnomad4 ASJ exome

AF:

0.0176

Gnomad4 EAS exome

AF:

0.146

Gnomad4 SAS exome

AF:

0.0803

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0271

Gnomad4 OTH exome

AF:

0.0348

GnomAD4 genome

AF:

0.0298

AC:

4533

AN:

152200

Hom.:

136

Cov.:

AF XY:

0.0315

AC XY:

2347

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00780

Gnomad4 AMR

AF:

0.0382

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.157

Gnomad4 SAS

AF:

0.0973

Gnomad4 FIN

AF:

0.0273

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0266

Alfa

AF:

0.0146

Hom.:

Bravo

AF:

0.0297

Asia WGS

AF:

0.113

AC:

393

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2016	- -

not provided

Benign:2

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	-	- -

Epiphyseal dysplasia, multiple, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.34

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.030

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