1-40304805-T-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein 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:4
• Conservation: PhyloP100: -0.228

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 -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, 9 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 [Likely_benign]. Clinvar id is 258366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40304805-T-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.1150A>C	p.Met384Leu	missense_variant	22/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.1150A>C	p.Met384Leu	missense_variant	22/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.1453A>C		non_coding_transcript_exon_variant	21/31	1
COL9A2	ENST00000466267.1	n.115A>C		non_coding_transcript_exon_variant	2/11	5

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

GnomAD3 exomes AF: 0.00174 AC: 271 AN: 155948 Hom.: 3 AF XY: 0.00122 AC XY: 100 AN XY: 82044

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 SAS 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

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00153

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

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000887 Hom.: 1

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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: rs145327896; hg19: chr1-40770477;