rs2276456

chr12-47982192-A-Gchr12-47982192-A-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.2302-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,600,264 control chromosomes in the GnomAD database, including 125,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13122 hom., cov: 32)
  • Exomes 𝑓: 0.39 (112479 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09

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]

LOC105369752 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-47982192-A-G is Benign according to our data. Variant chr12-47982192-A-G is described in ClinVar as [Benign]. Clinvar id is 258226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47982192-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.2302-32T>C		intron_variant		ENST00000380518.8
LOC105369752	XR_944910.2	n.219-223A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.2302-32T>C		intron_variant		1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.2095-32T>C		intron_variant		1
COL2A1	ENST00000483376.1	n.480-32T>C		intron_variant, non_coding_transcript_variant		5
COL2A1	ENST00000493991.5	n.1226-32T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62045 AN: 151596 Hom.: 13106 Cov.: 32

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.385 AC: 96463 AN: 250682 Hom.: 19845 AF XY: 0.393 AC XY: 53193 AN XY: 135514

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.598

Gnomad SAS exome AF: 0.465

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.388 AC: 562406 AN: 1448552 Hom.: 112479 Cov.: 31 AF XY: 0.391 AC XY: 282214 AN XY: 721458

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.568

Gnomad4 SAS exome AF: 0.462

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.380

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.409 AC: 62095 AN: 151712 Hom.: 13122 Cov.: 32 AF XY: 0.405 AC XY: 29999 AN XY: 74120

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.407

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.409

Alfa AF: 0.390 Hom.: 12224

Bravo AF: 0.418

Asia WGS AF: 0.465 AC: 1617 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 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	-0.88
Cadd	Benign	8.2
Dann	Benign	0.49

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: rs2276456; hg19: chr12-48375975;