12-47975548-C-T

Variant names:

• chr12-47975548-C-T
• rs760093841
• NM_001844.5:c.3655G>A
• COL2A1 p.Asp1219Asn

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_001844.5(COL2A1):​c.3655G>A​(p.Asp1219Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1219Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.94
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics, ClinGen
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen
• platyspondylic dysplasia, Torrance type

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• 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: Illumina, ClinGen, 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spondyloepiphyseal dysplasia, Stanescu type

  Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-47975548-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392316.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

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.3655G>A	p.Asp1219Asn	missense	Exon 51 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.3448G>A	p.Asp1150Asn	missense	Exon 50 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.3655G>A	p.Asp1219Asn	missense	Exon 51 of 54	ENSP00000369889.3	P02458-2
	COL2A1	ENST00000337299.7	TSL:1	c.3448G>A	p.Asp1150Asn	missense	Exon 50 of 53	ENSP00000338213.6	P02458-1
	COL2A1	ENST00000546974.1	TSL:1	n.508G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243472 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453020 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Stickler syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.078	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.42
gMVP		0.92
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs760093841;

hg19: chr12-48369331;