NM_001844.5:c.4068C>T

Variant names:

• chr12-47974681-G-A
• rs17122498
• NM_001844.5:c.4068C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001844.5(COL2A1):​c.4068C>T​(p.Gly1356Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,106 control chromosomes in the GnomAD database, including 1,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (422 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (643 hom.)
• Consequence: COL2A1 NM_001844.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.278
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-47974681-G-A is Benign according to our data. Variant chr12-47974681-G-A is described in ClinVar as Benign. ClinVar VariationId is 258235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.4068C>T	p.Gly1356Gly	synonymous_variant	Exon 52 of 54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.4068C>T	p.Gly1356Gly	synonymous_variant	Exon 52 of 54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.3861C>T	p.Gly1287Gly	synonymous_variant	Exon 51 of 53	1		ENSP00000338213.6
COL2A1	ENST00000493991.5	n.3154C>T		non_coding_transcript_exon_variant	Exon 35 of 37	2

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6516 AN: 152146 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0202 AC: 5087 AN: 251476 AF XY: 0.0198

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00879 AC: 12854 AN: 1461842 Hom.: 643 Cov.: 32 AF XY: 0.00998 AC XY: 7257 AN XY: 727222

African (AFR) AF: 0.141 AC: 4735 AN: 33472

American (AMR) AF: 0.0102 AC: 456 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.00368 AC: 146 AN: 39700

South Asian (SAS) AF: 0.0658 AC: 5671 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5766

European-Non Finnish (NFE) AF: 0.000666 AC: 741 AN: 1111982

Other (OTH) AF: 0.0165 AC: 999 AN: 60396

GnomAD4 genome AF: 0.0430 AC: 6542 AN: 152264 Hom.: 422 Cov.: 32 AF XY: 0.0428 AC XY: 3185 AN XY: 74448

African (AFR) AF: 0.137 AC: 5671 AN: 41512

American (AMR) AF: 0.0213 AC: 326 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00656 AC: 34 AN: 5186

South Asian (SAS) AF: 0.0794 AC: 383 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68034

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0238 Hom.: 386

Bravo AF: 0.0467

Asia WGS AF: 0.0750 AC: 262 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2016

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 provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Stickler syndrome type 1 Benign:1

Jan 13, 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 13, 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	-0.38
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.28
Mutation Taster		=84/16	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: rs17122498; hg19: chr12-48368464;