1-40307503-G-C

Variant names:

• chr1-40307503-G-C
• rs118135975
• NM_001852.4:c.955-4C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001852.4(COL9A2):​c.955-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,613,626 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 32)
  • Exomes 𝑓: 0.021 (421 hom.)
• Consequence: COL9A2 NM_001852.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004741
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.131
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-40307503-G-C is Benign according to our data. Variant chr1-40307503-G-C is described in ClinVar as Benign. ClinVar VariationId is 258397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0176 (2677/152320) while in subpopulation SAS AF = 0.033 (159/4822). AF 95% confidence interval is 0.0288. There are 45 homozygotes in GnomAd4. There are 1380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001852.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	NM_001852.4	MANE Select	c.955-4C>G		splice_region intron	N/A	NP_001843.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.955-4C>G		splice_region intron	N/A	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.1258-4C>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2677 AN: 152204 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0271 AC: 6808 AN: 251116 AF XY: 0.0266

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.0530

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.0223

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0209 AC: 30498 AN: 1461306 Hom.: 421 Cov.: 33 AF XY: 0.0216 AC XY: 15666 AN XY: 726946

African (AFR) AF: 0.00314 AC: 105 AN: 33478

American (AMR) AF: 0.0489 AC: 2185 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 1070 AN: 26126

East Asian (EAS) AF: 0.0329 AC: 1304 AN: 39694

South Asian (SAS) AF: 0.0349 AC: 3009 AN: 86222

European-Finnish (FIN) AF: 0.0250 AC: 1337 AN: 53410

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20183 AN: 1111540

Other (OTH) AF: 0.0202 AC: 1219 AN: 60380

GnomAD4 genome AF: 0.0176 AC: 2677 AN: 152320 Hom.: 45 Cov.: 32 AF XY: 0.0185 AC XY: 1380 AN XY: 74464

African (AFR) AF: 0.00332 AC: 138 AN: 41560

American (AMR) AF: 0.0250 AC: 382 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3472

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5182

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4822

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1440 AN: 68034

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0238 Hom.: 13

Bravo AF: 0.0166

Asia WGS AF: 0.0310 AC: 107 AN: 3478

EpiCase AF: 0.0198

EpiControl AF: 0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 30, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:4

Mar 11, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epiphyseal dysplasia, multiple, 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 12, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.3
DANN	Benign	0.65
PhyloP100		-0.13
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs118135975; hg19: chr1-40773175; COSMIC: COSV65607253; COSMIC: COSV65607253;