1-40303912-T-C

Position:

• chr1-40303912-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001852.4(COL9A2):​c.1368+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,551,628 control chromosomes in the GnomAD database, including 1,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (668 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1062 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.33

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 (BayesDel_noAF=-0.95).
• BP6: Variant 1-40303912-T-C is Benign according to our data. Variant chr1-40303912-T-C is described in ClinVar as [Benign]. Clinvar id is 258374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40303912-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.1368+16A>G		intron_variant		ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.1368+16A>G		intron_variant		1	NM_001852.4	ENSP00000361834	P1
COL9A2	ENST00000482722.5	n.1671+16A>G		intron_variant, non_coding_transcript_variant		1
COL9A2	ENST00000427563.1	n.179+16A>G		intron_variant, non_coding_transcript_variant		3
COL9A2	ENST00000466267.1	n.333+16A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0673 AC: 10223 AN: 151878 Hom.: 660 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0259

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0216

Gnomad OTH AF: 0.0446

GnomAD3 exomes AF: 0.0389 AC: 5724 AN: 147276 Hom.: 228 AF XY: 0.0366 AC XY: 2895 AN XY: 79018

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0587

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.0220

Gnomad SAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0258 AC: 36170 AN: 1399634 Hom.: 1062 Cov.: 34 AF XY: 0.0259 AC XY: 17882 AN XY: 690494

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.0557

Gnomad4 ASJ exome AF: 0.0407

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0253

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0675 AC: 10262 AN: 151994 Hom.: 668 Cov.: 32 AF XY: 0.0675 AC XY: 5019 AN XY: 74308

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0427

Gnomad4 ASJ AF: 0.0406

Gnomad4 EAS AF: 0.0259

Gnomad4 SAS AF: 0.0338

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0216

Gnomad4 OTH AF: 0.0475

Alfa AF: 0.0485 Hom.: 58

Bravo AF: 0.0735

Asia WGS AF: 0.0680 AC: 234 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.42
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6684531; hg19: chr1-40769584;