rs1635550

Variant names:

• chr12-47984187-A-G
• rs1635550
• NM_001844.5:c.1888-47T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-47984187-A-G
• chr12-47984187-A-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.1888-47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,574,222 control chromosomes in the GnomAD database, including 507,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42882 hom., cov: 32)
  • Exomes 𝑓: 0.81 (465052 hom.)
• Consequence: COL2A1 NM_001844.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.817
• Publications: 12 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=-0.88).
• BP6: Variant 12-47984187-A-G is Benign according to our data. Variant chr12-47984187-A-G is described in ClinVar as Benign. ClinVar VariationId is 258219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.1888-47T>C		intron_variant	Intron 28 of 53	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.1888-47T>C		intron_variant	Intron 28 of 53	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.1681-47T>C		intron_variant	Intron 27 of 52	1		ENSP00000338213.6
COL2A1	ENST00000493991.5	n.812-47T>C		intron_variant	Intron 11 of 36	2

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113276 AN: 151952 Hom.: 42857 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.740 AC: 164232 AN: 221870 AF XY: 0.752

Gnomad AFR exome AF: 0.639

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.772

Gnomad EAS exome AF: 0.625

Gnomad FIN exome AF: 0.746

Gnomad NFE exome AF: 0.831

Gnomad OTH exome AF: 0.775

GnomAD4 exome AF: 0.805 AC: 1145485 AN: 1422152 Hom.: 465052 Cov.: 25 AF XY: 0.805 AC XY: 569529 AN XY: 707216

African (AFR) AF: 0.634 AC: 20803 AN: 32810

American (AMR) AF: 0.559 AC: 23710 AN: 42384

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 19967 AN: 25618

East Asian (EAS) AF: 0.609 AC: 23863 AN: 39164

South Asian (SAS) AF: 0.744 AC: 61695 AN: 82904

European-Finnish (FIN) AF: 0.753 AC: 39282 AN: 52136

Middle Eastern (MID) AF: 0.822 AC: 4688 AN: 5706

European-Non Finnish (NFE) AF: 0.836 AC: 904828 AN: 1082470

Other (OTH) AF: 0.791 AC: 46649 AN: 58960

GnomAD4 genome AF: 0.745 AC: 113344 AN: 152070 Hom.: 42882 Cov.: 32 AF XY: 0.740 AC XY: 55043 AN XY: 74348

African (AFR) AF: 0.640 AC: 26533 AN: 41452

American (AMR) AF: 0.671 AC: 10248 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 2695 AN: 3468

East Asian (EAS) AF: 0.628 AC: 3250 AN: 5172

South Asian (SAS) AF: 0.730 AC: 3524 AN: 4828

European-Finnish (FIN) AF: 0.755 AC: 7989 AN: 10580

Middle Eastern (MID) AF: 0.798 AC: 233 AN: 292

European-Non Finnish (NFE) AF: 0.834 AC: 56691 AN: 67978

Other (OTH) AF: 0.751 AC: 1590 AN: 2116

Alfa AF: 0.795 Hom.: 62759

Bravo AF: 0.732

Asia WGS AF: 0.640 AC: 2229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 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

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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	0.16
DANN	Benign	0.30
PhyloP100		-0.82
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs1635550; hg19: chr12-48377970; COSMIC: COSV61531353; COSMIC: COSV61531353;