NM_001844.5:c.3991G>A

Variant names:

• chr12-47974758-C-T
• rs12721427
• NM_001844.5:c.3991G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.3991G>A​(p.Val1331Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,614,076 control chromosomes in the GnomAD database, including 4,355 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (288 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4067 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.08
• Publications: 24 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• COL2A1-related spondyloepiphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dysplasia of the proximal femoral epiphyses

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

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

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

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

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

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

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

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• otospondylomegaepiphyseal dysplasia, autosomal recessive

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

  Inheritance: Unknown, 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001844.5
• PP2: Missense variant in the COL2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 376 curated pathogenic missense variants (we use a threshold of 10). The gene has 125 curated benign missense variants. Gene score misZ: 3.2926 (above the threshold of 3.09). Trascript score misZ: 5.3726 (above the threshold of 3.09). GenCC associations: The gene is linked to spondyloepiphyseal dysplasia with metatarsal shortening, Stickler syndrome type 1, multiple epiphyseal dysplasia, Beighton type, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, familial avascular necrosis of femoral head, Kniest dysplasia, spondyloepiphyseal dysplasia congenita, spondyloperipheral dysplasia, hypochondrogenesis, achondrogenesis type II, Legg-Calve-Perthes disease, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Schmidt type, dysplasia of the proximal femoral epiphyses, otospondylomegaepiphyseal dysplasia, autosomal recessive, spondylometaphyseal dysplasia, otospondylomegaepiphyseal dysplasia, avascular necrosis of femoral head, primary, 1, spondyloepiphyseal dysplasia, Stanescu type, vitreoretinopathy with phalangeal epiphyseal dysplasia, platyspondylic dysplasia, Torrance type, Stickler syndrome, type I, nonsyndromic ocular, dysspondyloenchondromatosis, COL2A1-related spondyloepiphyseal dysplasia, autosomal dominant rhegmatogenous retinal detachment.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019786358).
• BP6: Variant 12-47974758-C-T is Benign according to our data. Variant chr12-47974758-C-T is described in ClinVar as Benign. ClinVar VariationId is 258234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001844.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	NM_001844.5	MANE Select	c.3991G>A	p.Val1331Ile	missense	Exon 52 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.3784G>A	p.Val1262Ile	missense	Exon 51 of 53	NP_149162.2	P02458-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL2A1	ENST00000380518.8	TSL:1 MANE Select	c.3991G>A	p.Val1331Ile	missense	Exon 52 of 54	ENSP00000369889.3	P02458-2
	COL2A1	ENST00000337299.7	TSL:1	c.3784G>A	p.Val1262Ile	missense	Exon 51 of 53	ENSP00000338213.6	P02458-1
	COL2A1	ENST00000928357.1		c.3994G>A	p.Val1332Ile	missense	Exon 52 of 54	ENSP00000598416.1

Frequencies

GnomAD3 genomes AF: 0.0524 AC: 7968 AN: 152114 Hom.: 289 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0535 AC: 13459 AN: 251492 AF XY: 0.0537

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0167

Gnomad FIN exome AF: 0.0904

Gnomad NFE exome AF: 0.0777

Gnomad OTH exome AF: 0.0559

GnomAD4 exome AF: 0.0702 AC: 102563 AN: 1461844 Hom.: 4067 Cov.: 33 AF XY: 0.0689 AC XY: 50122 AN XY: 727230

African (AFR) AF: 0.0154 AC: 515 AN: 33480

American (AMR) AF: 0.0259 AC: 1160 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 561 AN: 26136

East Asian (EAS) AF: 0.0203 AC: 807 AN: 39700

South Asian (SAS) AF: 0.0218 AC: 1884 AN: 86258

European-Finnish (FIN) AF: 0.0904 AC: 4831 AN: 53418

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5768

European-Non Finnish (NFE) AF: 0.0802 AC: 89168 AN: 1111966

Other (OTH) AF: 0.0585 AC: 3531 AN: 60394

GnomAD4 genome AF: 0.0523 AC: 7963 AN: 152232 Hom.: 288 Cov.: 32 AF XY: 0.0523 AC XY: 3893 AN XY: 74428

African (AFR) AF: 0.0188 AC: 780 AN: 41546

American (AMR) AF: 0.0300 AC: 459 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.0164 AC: 85 AN: 5176

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4826

European-Finnish (FIN) AF: 0.0924 AC: 978 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0792 AC: 5384 AN: 68012

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0643 Hom.: 1587

Bravo AF: 0.0456

TwinsUK AF: 0.0796 AC: 295

ALSPAC AF: 0.0874 AC: 337

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.0707 AC: 608

ExAC AF: 0.0549 AC: 6665

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0664

EpiControl AF: 0.0696

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Stickler syndrome type 1 (1)
-	-	1	Type II Collagenopathies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.11
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		2.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.91	T
Polyphen		0.0010	B
Vest4		0.043
MPC		0.26
ClinPred		0.0088	T
GERP RS		4.9
Varity_R		0.048
gMVP		0.34
Mutation Taster		=95/5	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: rs12721427; hg19: chr12-48368541; COSMIC: COSV61531019; COSMIC: COSV61531019;