rs2228565

chr1-40310265-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001852.4(COL9A2):c.737C>T(p.Thr246Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,614,028 control chromosomes in the GnomAD database, including 1,056 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T246T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (61 hom., cov: 32)
  • Exomes 𝑓: 0.033 (995 hom.)
• Consequence: COL9A2 NM_001852.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001059
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.167

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078905225).
• BP6: Variant 1-40310265-G-A is Benign according to our data. Variant chr1-40310265-G-A is described in ClinVar as [Benign]. Clinvar id is 258393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40310265-G-A is described in Lovd as [Benign]. Variant chr1-40310265-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3261/152252) while in subpopulation NFE AF= 0.0339 (2304/67998). AF 95% confidence interval is 0.0327. There are 61 homozygotes in gnomad4. There are 1536 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.737C>T	p.Thr246Met	missense_variant, splice_region_variant	14/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.737C>T	p.Thr246Met	missense_variant, splice_region_variant	14/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.1040C>T		splice_region_variant, non_coding_transcript_exon_variant	13/31	1
COL9A2	ENST00000488463.6	n.788C>T		splice_region_variant, non_coding_transcript_exon_variant	13/14	5
COL9A2	ENST00000417105.6			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3262 AN: 152134 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0218 AC: 5493 AN: 251406 Hom.: 93 AF XY: 0.0219 AC XY: 2977 AN XY: 135872

Gnomad AFR exome AF: 0.00708

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00523

Gnomad FIN exome AF: 0.0379

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0331 AC: 48426 AN: 1461776 Hom.: 995 Cov.: 34 AF XY: 0.0323 AC XY: 23512 AN XY: 727204

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00654

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00538

Gnomad4 FIN exome AF: 0.0367

Gnomad4 NFE exome AF: 0.0389

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0214 AC: 3261 AN: 152252 Hom.: 61 Cov.: 32 AF XY: 0.0206 AC XY: 1536 AN XY: 74432

Gnomad4 AFR AF: 0.00631

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0388

Gnomad4 NFE AF: 0.0339

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0295 Hom.: 110

Bravo AF: 0.0202

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.0345 AC: 297

ExAC AF: 0.0222 AC: 2694

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0322

EpiControl AF: 0.0300

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Epiphyseal dysplasia, multiple, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.18
Dann	Benign	0.60
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Benign	0.22	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.17
MPC		0.77
ClinPred		0.014	T
GERP RS		-9.3
Varity_R		0.026
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.044
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

Other links and lift over

dbSNP: rs2228565; hg19: chr1-40775937;