rs11168338

chr12-47983186-C-Achr12-47983186-C-T

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.2050-49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,592,990 control chromosomes in the GnomAD database, including 83,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5759 hom., cov: 33)
  • Exomes 𝑓: 0.32 (78166 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44

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=-0.83).
• BP6: Variant 12-47983186-C-A is Benign according to our data. Variant chr12-47983186-C-A is described in ClinVar as [Benign]. Clinvar id is 258221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47983186-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.2050-49G>T		intron_variant		ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.2050-49G>T		intron_variant		1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.1843-49G>T		intron_variant		1
COL2A1	ENST00000483376.1	n.228-49G>T		intron_variant, non_coding_transcript_variant		5
COL2A1	ENST00000493991.5	n.974-49G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37225 AN: 152034 Hom.: 5758 Cov.: 33

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.279 AC: 62479 AN: 223872 Hom.: 9824 AF XY: 0.285 AC XY: 34487 AN XY: 120846

Gnomad AFR exome AF: 0.0582

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.0257

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.321 AC: 462665 AN: 1440838 Hom.: 78166 Cov.: 31 AF XY: 0.320 AC XY: 229285 AN XY: 716034

Gnomad4 AFR exome AF: 0.0529

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.350

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.245 AC: 37236 AN: 152152 Hom.: 5759 Cov.: 33 AF XY: 0.244 AC XY: 18129 AN XY: 74390

Gnomad4 AFR AF: 0.0644

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.326

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.262

Alfa AF: 0.312 Hom.: 4477

Bravo AF: 0.232

Asia WGS AF: 0.148 AC: 519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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	-0.83
Cadd	Benign	0.10
Dann	Benign	0.76

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: rs11168338; hg19: chr12-48376969;