rs1793958

Positions:

• chr12-47998650-A-G

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.293-219T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 574,194 control chromosomes in the GnomAD database, including 98,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24890 hom., cov: 31)
  • Exomes 𝑓: 0.58 (73498 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120

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=-0.56).
• BP6: Variant 12-47998650-A-G is Benign according to our data. Variant chr12-47998650-A-G is described in ClinVar as [Benign]. Clinvar id is 677845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.293-219T>C		intron_variant		ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.293-219T>C		intron_variant		1	NM_001844.5	ENSP00000369889	P1
COL2A1	ENST00000337299.7	c.86-219T>C		intron_variant		1		ENSP00000338213
COL2A1	ENST00000466884.1	n.210T>C		non_coding_transcript_exon_variant	1/2	5
COL2A1	ENST00000474996.6	n.531-219T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86038 AN: 151830 Hom.: 24872 Cov.: 31

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.550

GnomAD4 exome AF: 0.582 AC: 245612 AN: 422246 Hom.: 73498 Cov.: 3 AF XY: 0.582 AC XY: 129461 AN XY: 222574

Gnomad4 AFR exome AF: 0.543

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.535

Gnomad4 EAS exome AF: 0.283

Gnomad4 SAS exome AF: 0.569

Gnomad4 FIN exome AF: 0.585

Gnomad4 NFE exome AF: 0.630

Gnomad4 OTH exome AF: 0.568

GnomAD4 genome AF: 0.567 AC: 86095 AN: 151948 Hom.: 24890 Cov.: 31 AF XY: 0.561 AC XY: 41692 AN XY: 74266

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.527

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.584

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.547

Alfa AF: 0.606 Hom.: 25715

Bravo AF: 0.553

Asia WGS AF: 0.407 AC: 1422 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.56
CADD	Benign	8.0
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1793958; hg19: chr12-48392433;