12-47974345-G-C

Position:

• chr12-47974345-G-C

Variant summary

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

The ENST00000380518.8(COL2A1):​c.4075-14C>G 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 0.0684 in 1,613,128 control chromosomes in the GnomAD database, including 4,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (288 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4064 hom.)
• Consequence: COL2A1 ENST00000380518.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.592

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-47974345-G-C is Benign according to our data. Variant chr12-47974345-G-C is described in ClinVar as [Benign]. Clinvar id is 258236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47974345-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.4075-14C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.4075-14C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.3868-14C>G		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000338213
COL2A1	ENST00000493991.5	n.3161-14C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0524 AC: 7974 AN: 152144 Hom.: 289 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0793

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0534 AC: 13355 AN: 250174 Hom.: 478 AF XY: 0.0536 AC XY: 7249 AN XY: 135246

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0167

Gnomad SAS exome AF: 0.0223

Gnomad FIN exome AF: 0.0915

Gnomad NFE exome AF: 0.0776

Gnomad OTH exome AF: 0.0555

GnomAD4 exome AF: 0.0701 AC: 102431 AN: 1460866 Hom.: 4064 Cov.: 35 AF XY: 0.0689 AC XY: 50068 AN XY: 726690

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.0259

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.0204

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.0906

Gnomad4 NFE exome AF: 0.0801

Gnomad4 OTH exome AF: 0.0584

GnomAD4 genome AF: 0.0523 AC: 7969 AN: 152262 Hom.: 288 Cov.: 32 AF XY: 0.0523 AC XY: 3894 AN XY: 74452

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0920

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0442 Hom.: 49

Bravo AF: 0.0456

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Stickler syndrome type 1 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. -

Type II Collagenopathies 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12721425; hg19: chr12-48368128; COSMIC: COSV61529846; COSMIC: COSV61529846;