12-48004219-G-C

Position:

• chr12-48004219-G-C

Variant summary

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

The NM_001844.5(COL2A1):​c.85+18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,525,864 control chromosomes in the GnomAD database, including 502,979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44139 hom., cov: 32)
  • Exomes 𝑓: 0.81 (458840 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.21

Genes affected

COL2A1 (HGNC:2200): (collagen type II alpha 1 chain) This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

COL2A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-48004219-G-C is Benign according to our data. Variant chr12-48004219-G-C is described in ClinVar as [Benign]. Clinvar id is 93791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48004219-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.85+18C>G		intron_variant		ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.85+18C>G		intron_variant		1	NM_001844.5	ENSP00000369889.3

Frequencies

GnomAD3 genomes AF: 0.757 AC: 114993 AN: 151942 Hom.: 44118 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.767

GnomAD3 exomes AF: 0.741 AC: 113190 AN: 152666 Hom.: 43042 AF XY: 0.753 AC XY: 60823 AN XY: 80760

Gnomad AFR exome AF: 0.666

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.790

Gnomad EAS exome AF: 0.601

Gnomad SAS exome AF: 0.766

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.839

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.814 AC: 1118153 AN: 1373804 Hom.: 458840 Cov.: 24 AF XY: 0.814 AC XY: 552391 AN XY: 678884

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.794

Gnomad4 EAS exome AF: 0.570

Gnomad4 SAS exome AF: 0.765

Gnomad4 FIN exome AF: 0.757

Gnomad4 NFE exome AF: 0.843

Gnomad4 OTH exome AF: 0.796

GnomAD4 genome AF: 0.757 AC: 115064 AN: 152060 Hom.: 44139 Cov.: 32 AF XY: 0.750 AC XY: 55778 AN XY: 74350

Gnomad4 AFR AF: 0.668

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.803

Gnomad4 EAS AF: 0.598

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.756

Gnomad4 NFE AF: 0.839

Gnomad4 OTH AF: 0.763

Alfa AF: 0.775 Hom.: 5545

Bravo AF: 0.743

Asia WGS AF: 0.655 AC: 2280 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Eurofins Ntd Llc (ga)	Jul 25, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Nov 03, 2017	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.37

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: rs3803184; hg19: chr12-48398002; COSMIC: COSV61529862; COSMIC: COSV61529862;