rs2229826

chr1-40301251-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001852.4(COL9A2):c.2001C>T(p.Ala667=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,132 control chromosomes in the GnomAD database, including 545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (28 hom., cov: 32)
  • Exomes 𝑓: 0.024 (517 hom.)
• Consequence: COL9A2 NM_001852.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.65

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-40301251-G-A is Benign according to our data. Variant chr1-40301251-G-A is described in ClinVar as [Benign]. Clinvar id is 258383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40301251-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2631/152316) while in subpopulation NFE AF= 0.024 (1635/68032). AF 95% confidence interval is 0.0231. There are 28 homozygotes in gnomad4. There are 1334 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.2001C>T	p.Ala667=	synonymous_variant	32/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.2001C>T	p.Ala667=	synonymous_variant	32/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.2304C>T		non_coding_transcript_exon_variant	31/31	1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2630 AN: 152198 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0177 AC: 4414 AN: 249702 Hom.: 75 AF XY: 0.0178 AC XY: 2411 AN XY: 135242

Gnomad AFR exome AF: 0.00466

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0240 AC: 35049 AN: 1461816 Hom.: 517 Cov.: 31 AF XY: 0.0239 AC XY: 17402 AN XY: 727220

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0173 AC: 2631 AN: 152316 Hom.: 28 Cov.: 32 AF XY: 0.0179 AC XY: 1334 AN XY: 74488

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0513

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0201 Hom.: 20

Bravo AF: 0.0135

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0223

EpiControl AF: 0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	4.7
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2229826; hg19: chr1-40766923;