rs11168338

Variant names:

• chr12-47983186-C-A
• rs11168338
• NM_001844.5:c.2050-49G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47983186-C-A
• chr12-47983186-C-T

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.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:3
• Conservation: PhyloP100: -2.44
• Publications: 6 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)

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.2050-49G>T		intron_variant	Intron 31 of 53	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.2050-49G>T		intron_variant	Intron 31 of 53	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.1843-49G>T		intron_variant	Intron 30 of 52	1		ENSP00000338213.6
COL2A1	ENST00000483376.1	n.228-49G>T		intron_variant	Intron 2 of 7	5
COL2A1	ENST00000493991.5	n.974-49G>T		intron_variant	Intron 14 of 36	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

GnomAD2 exomes AF: 0.279 AC: 62479 AN: 223872 AF XY: 0.285

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 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

African (AFR) AF: 0.0529 AC: 1745 AN: 32992

American (AMR) AF: 0.261 AC: 11129 AN: 42584

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 7978 AN: 25694

East Asian (EAS) AF: 0.0290 AC: 1132 AN: 39016

South Asian (SAS) AF: 0.257 AC: 21595 AN: 84150

European-Finnish (FIN) AF: 0.309 AC: 16212 AN: 52510

Middle Eastern (MID) AF: 0.266 AC: 1527 AN: 5742

European-Non Finnish (NFE) AF: 0.350 AC: 384045 AN: 1098504

Other (OTH) AF: 0.290 AC: 17302 AN: 59646

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

African (AFR) AF: 0.0644 AC: 2676 AN: 41548

American (AMR) AF: 0.273 AC: 4171 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3468

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5182

South Asian (SAS) AF: 0.232 AC: 1120 AN: 4818

European-Finnish (FIN) AF: 0.326 AC: 3447 AN: 10584

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23636 AN: 67954

Other (OTH) AF: 0.262 AC: 551 AN: 2102

Alfa AF: 0.313 Hom.: 4884

Bravo AF: 0.232

Asia WGS AF: 0.148 AC: 519 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.83
CADD	Benign	0.10
DANN	Benign	0.76
PhyloP100		-2.4
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: rs11168338; hg19: chr12-48376969;