chr1-40312128-T-G

Position:

• chr1-40312128-T-G

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.364-16A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,593,676 control chromosomes in the GnomAD database, including 58,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7637 hom., cov: 31)
  • Exomes 𝑓: 0.25 (51322 hom.)
• Consequence: COL9A2 NM_001852.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.550

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=-0.83).
• BP6: Variant 1-40312128-T-G is Benign according to our data. Variant chr1-40312128-T-G is described in ClinVar as [Benign]. Clinvar id is 258387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40312128-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.364-16A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000372748.8	NP_001843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A2	ENST00000372748.8	c.364-16A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	ENSP00000361834	P1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44827 AN: 151352 Hom.: 7617 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.160

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.300 AC: 66243 AN: 220972 Hom.: 12155 AF XY: 0.288 AC XY: 34133 AN XY: 118632

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.249 AC: 358888 AN: 1442212 Hom.: 51322 Cov.: 33 AF XY: 0.248 AC XY: 177478 AN XY: 715728

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.722

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.296 AC: 44891 AN: 151464 Hom.: 7637 Cov.: 31 AF XY: 0.300 AC XY: 22159 AN XY: 73972

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.705

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.245

Alfa AF: 0.162 Hom.: 410

Bravo AF: 0.312

Asia WGS AF: 0.465 AC: 1617 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Feb 01, 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	-0.83
CADD	Benign	0.99
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1979785; hg19: chr1-40777800;