chr1-40303916-C-T

Position:

• chr1-40303916-C-T

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+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0608 in 1,552,050 control chromosomes in the GnomAD database, including 3,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (224 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2861 hom.)
• Consequence: COL9A2 NM_001852.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.04

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=-0.87).
• BP6: Variant 1-40303916-C-T is Benign according to our data. Variant chr1-40303916-C-T is described in ClinVar as [Benign]. Clinvar id is 258373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40303916-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.1368+12G>A		intron_variant		ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.1368+12G>A		intron_variant		1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.1671+12G>A		intron_variant, non_coding_transcript_variant		1
COL9A2	ENST00000427563.1	n.179+12G>A		intron_variant, non_coding_transcript_variant		3
COL9A2	ENST00000466267.1	n.333+12G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7823 AN: 152092 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.0622

GnomAD3 exomes AF: 0.0538 AC: 7952 AN: 147756 Hom.: 268 AF XY: 0.0539 AC XY: 4271 AN XY: 79230

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.0595

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.00260

Gnomad SAS exome AF: 0.0431

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0584

GnomAD4 exome AF: 0.0619 AC: 86616 AN: 1399840 Hom.: 2861 Cov.: 34 AF XY: 0.0615 AC XY: 42469 AN XY: 690618

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.0561

Gnomad4 ASJ exome AF: 0.0804

Gnomad4 EAS exome AF: 0.00602

Gnomad4 SAS exome AF: 0.0433

Gnomad4 FIN exome AF: 0.0506

Gnomad4 NFE exome AF: 0.0664

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0514 AC: 7816 AN: 152210 Hom.: 224 Cov.: 32 AF XY: 0.0499 AC XY: 3710 AN XY: 74412

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.0552

Gnomad4 ASJ AF: 0.0821

Gnomad4 EAS AF: 0.00426

Gnomad4 SAS AF: 0.0368

Gnomad4 FIN AF: 0.0468

Gnomad4 NFE AF: 0.0624

Gnomad4 OTH AF: 0.0606

Alfa AF: 0.0591 Hom.: 55

Bravo AF: 0.0515

Asia WGS AF: 0.0210 AC: 72 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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	-	- -

Epiphyseal dysplasia, multiple, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.93

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: rs112370406; hg19: chr1-40769588;