rs4760608

Positions:

• chr12-47975206-A-C
• chr12-47975206-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001844.5(COL2A1):​c.3886+111T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,377,868 control chromosomes in the GnomAD database, including 30,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3020 hom., cov: 32)
  • Exomes 𝑓: 0.21 (27928 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0610

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-47975206-A-C is Benign according to our data. Variant chr12-47975206-A-C is described in ClinVar as [Benign]. Clinvar id is 675027.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.3886+111T>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.3886+111T>G		intron_variant		1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.3679+111T>G		intron_variant		1		ENSP00000338213
COL2A1	ENST00000493991.5	n.2972+111T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28852 AN: 151896 Hom.: 3020 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.208 AC: 254661 AN: 1225854 Hom.: 27928 AF XY: 0.207 AC XY: 126790 AN XY: 611178

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.292

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.211

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.190 AC: 28855 AN: 152014 Hom.: 3020 Cov.: 32 AF XY: 0.187 AC XY: 13908 AN XY: 74328

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.204

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.216

Alfa AF: 0.198 Hom.: 3257

Bravo AF: 0.192

Asia WGS AF: 0.224 AC: 780 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.1
DANN	Benign	0.73

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: rs4760608; hg19: chr12-48368989;