rs41272777

Variant names:

• chr12-47973271-G-A
• rs41272777
• NM_001844.5:c.*136C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47973271-G-A
• chr12-47973271-G-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.*136C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,171,608 control chromosomes in the GnomAD database, including 3,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (308 hom., cov: 32)
  • Exomes 𝑓: 0.068 (2770 hom.)
• Consequence: COL2A1 NM_001844.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.717
• Publications: 5 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=-0.48).
• BP6: Variant 12-47973271-G-A is Benign according to our data. Variant chr12-47973271-G-A is described in ClinVar as [Benign]. Clinvar id is 308898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.*136C>T		3_prime_UTR_variant	Exon 54 of 54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.*136C>T		3_prime_UTR_variant	Exon 54 of 54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000493991.5	n.3686C>T		non_coding_transcript_exon_variant	Exon 37 of 37	2
COL2A1	ENST00000337299.7	c.*136C>T		downstream_gene_variant		1		ENSP00000338213.6

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 8617 AN: 152068 Hom.: 308 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0464

GnomAD4 exome AF: 0.0685 AC: 69792 AN: 1019422 Hom.: 2770 Cov.: 14 AF XY: 0.0667 AC XY: 35020 AN XY: 524824

African (AFR) AF: 0.0316 AC: 778 AN: 24648

American (AMR) AF: 0.0266 AC: 1152 AN: 43294

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 505 AN: 23348

East Asian (EAS) AF: 0.0208 AC: 782 AN: 37614

South Asian (SAS) AF: 0.0221 AC: 1705 AN: 77306

European-Finnish (FIN) AF: 0.0908 AC: 4787 AN: 52724

Middle Eastern (MID) AF: 0.0190 AC: 90 AN: 4748

European-Non Finnish (NFE) AF: 0.0807 AC: 57336 AN: 710070

Other (OTH) AF: 0.0582 AC: 2657 AN: 45670

GnomAD4 genome AF: 0.0566 AC: 8619 AN: 152186 Hom.: 308 Cov.: 32 AF XY: 0.0565 AC XY: 4204 AN XY: 74394

African (AFR) AF: 0.0333 AC: 1385 AN: 41530

American (AMR) AF: 0.0322 AC: 492 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3470

East Asian (EAS) AF: 0.0166 AC: 86 AN: 5178

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4822

European-Finnish (FIN) AF: 0.0925 AC: 979 AN: 10584

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0793 AC: 5391 AN: 67992

Other (OTH) AF: 0.0459 AC: 97 AN: 2112

Alfa AF: 0.0656 Hom.: 142

Bravo AF: 0.0504

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stickler syndrome type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Type II Collagenopathies Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.7
DANN	Benign	0.81
PhyloP100		0.72
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: rs41272777; hg19: chr12-48367054; COSMIC: COSV56743793; COSMIC: COSV56743793;