rs6674856

Positions:

• chr1-40301906-A-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.1793-17T>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 0.0304 in 1,610,114 control chromosomes in the GnomAD database, including 1,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (734 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1203 hom.)
• Consequence: COL9A2 NM_001852.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.529

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=-0.88).
• BP6: Variant 1-40301906-A-G is Benign according to our data. Variant chr1-40301906-A-G is described in ClinVar as [Benign]. Clinvar id is 258378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40301906-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A2	NM_001852.4	c.1793-17T>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.1793-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001852.4	ENSP00000361834	P1
COL9A2	ENST00000482722.5	n.2096-17T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
COL9A2	ENST00000466267.1	n.758-17T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10579 AN: 152132 Hom.: 727 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0454

GnomAD3 exomes AF: 0.0405 AC: 9919 AN: 244810 Hom.: 418 AF XY: 0.0364 AC XY: 4818 AN XY: 132434

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0618

Gnomad ASJ exome AF: 0.0410

Gnomad EAS exome AF: 0.0226

Gnomad SAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0263 AC: 38390 AN: 1457864 Hom.: 1203 Cov.: 31 AF XY: 0.0262 AC XY: 19024 AN XY: 725182

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.0589

Gnomad4 ASJ exome AF: 0.0409

Gnomad4 EAS exome AF: 0.0330

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0250

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0697 AC: 10618 AN: 152250 Hom.: 734 Cov.: 32 AF XY: 0.0696 AC XY: 5185 AN XY: 74446

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0441

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.0262

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0496 Hom.: 67

Bravo AF: 0.0760

Asia WGS AF: 0.0660 AC: 228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6674856; hg19: chr1-40767578; COSMIC: COSV65622340; COSMIC: COSV65622340;