12-47982192-A-G

Variant names:

• chr12-47982192-A-G
• rs2276456
• NM_001844.5:c.2302-32T>C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 1.09
• Publications: 11 publications found

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]

COL2A1 Gene-Disease associations (from GenCC):

• achondrogenesis type II

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Kniest dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• platyspondylic dysplasia, Torrance type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• spondyloepimetaphyseal dysplasia, Strudwick type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• spondyloepiphyseal dysplasia congenita

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia with metatarsal shortening

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• spondylometaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondyloperipheral dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Stickler syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Illumina, Orphanet, Genomics England PanelApp
• Stickler syndrome, type I, nonsyndromic ocular

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• avascular necrosis of femoral head, primary, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Legg-Calve-Perthes disease

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia, Stanescu type

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant rhegmatogenous retinal detachment

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dysspondyloenchondromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial avascular necrosis of femoral head

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple epiphyseal dysplasia, Beighton type

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• spondylometaphyseal dysplasia, Schmidt type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• otospondylomegaepiphyseal dysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• vitreoretinopathy with phalangeal epiphyseal dysplasia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

LOC105369752 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 258226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.2302-32T>C		intron_variant	Intron 34 of 53	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.2302-32T>C		intron_variant	Intron 34 of 53	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.2095-32T>C		intron_variant	Intron 33 of 52	1		ENSP00000338213.6
COL2A1	ENST00000483376.1	n.480-32T>C		intron_variant	Intron 5 of 7	5
COL2A1	ENST00000493991.5	n.1226-32T>C		intron_variant	Intron 17 of 36	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

GnomAD2 exomes AF: 0.385 AC: 96463 AN: 250682 AF XY: 0.393

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 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

African (AFR) AF: 0.495 AC: 16441 AN: 33208

American (AMR) AF: 0.254 AC: 11350 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 10694 AN: 26054

East Asian (EAS) AF: 0.568 AC: 22499 AN: 39618

South Asian (SAS) AF: 0.462 AC: 39738 AN: 85980

European-Finnish (FIN) AF: 0.300 AC: 15890 AN: 53032

Middle Eastern (MID) AF: 0.492 AC: 2811 AN: 5714

European-Non Finnish (NFE) AF: 0.380 AC: 418316 AN: 1100286

Other (OTH) AF: 0.411 AC: 24667 AN: 59966

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

African (AFR) AF: 0.489 AC: 20218 AN: 41368

American (AMR) AF: 0.343 AC: 5240 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3024 AN: 5122

South Asian (SAS) AF: 0.467 AC: 2249 AN: 4814

European-Finnish (FIN) AF: 0.284 AC: 2989 AN: 10540

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25716 AN: 67830

Other (OTH) AF: 0.409 AC: 860 AN: 2104

Alfa AF: 0.392 Hom.: 15946

Bravo AF: 0.418

Asia WGS AF: 0.465 AC: 1617 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.2
DANN	Benign	0.49
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2276456; hg19: chr12-48375975;