1-40304805-T-G

Variant names:

• chr1-40304805-T-G
• rs145327896
• NM_001852.4:c.1150A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001852.4(COL9A2):​c.1150A>C​(p.Met384Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,550,918 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0070 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (13 hom.)
• Consequence: COL9A2 NM_001852.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.228
• 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001852.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.00675714).
• BP6: Variant 1-40304805-T-G is Benign according to our data. Variant chr1-40304805-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00699 (1064/152292) while in subpopulation AFR AF = 0.0233 (967/41576). AF 95% confidence interval is 0.022. There are 9 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1150A>C	p.Met384Leu	missense	Exon 22 of 32	NP_001843.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A2	ENST00000372748.8	TSL:1 MANE Select	c.1150A>C	p.Met384Leu	missense	Exon 22 of 32	ENSP00000361834.3
	COL9A2	ENST00000482722.5	TSL:1	n.1453A>C		non_coding_transcript_exon	Exon 21 of 31
	COL9A2	ENST00000466267.1	TSL:5	n.115A>C		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes AF: 0.00700 AC: 1065 AN: 152172 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00174 AC: 271 AN: 155948 AF XY: 0.00122

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000825

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000699 AC: 977 AN: 1398626 Hom.: 13 Cov.: 31 AF XY: 0.000583 AC XY: 402 AN XY: 689878

African (AFR) AF: 0.0237 AC: 750 AN: 31598

American (AMR) AF: 0.00182 AC: 65 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35754

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48650

Middle Eastern (MID) AF: 0.000879 AC: 5 AN: 5688

European-Non Finnish (NFE) AF: 0.0000612 AC: 66 AN: 1078864

Other (OTH) AF: 0.00153 AC: 89 AN: 58002

GnomAD4 genome AF: 0.00699 AC: 1064 AN: 152292 Hom.: 9 Cov.: 32 AF XY: 0.00673 AC XY: 501 AN XY: 74460

African (AFR) AF: 0.0233 AC: 967 AN: 41576

American (AMR) AF: 0.00458 AC: 70 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68022

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00145 Hom.: 5

Bravo AF: 0.00771

ESP6500AA AF: 0.0206 AC: 85

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 91

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

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

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Connective tissue disorder Benign:1

May 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.5
DANN	Benign	0.74
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.91	L
PhyloP100		-0.23
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.23
Sift	Benign	0.32	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.45		Loss of MoRF binding (P = 0.1389)
MVP		0.55
MPC		0.26
ClinPred		0.0018	T
GERP RS		-5.8
Varity_R		0.098
gMVP		0.12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs145327896; hg19: chr1-40770477; COSMIC: COSV106110454; COSMIC: COSV106110454;