rs3803183

Variant names:

• chr12-48004297-T-A
• rs3803183
• NM_001844.5:c.25A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-48004297-T-A
• chr12-48004297-T-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001844.5(COL2A1):​c.25A>T​(p.Thr9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,549,070 control chromosomes in the GnomAD database, including 511,699 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.76 (44143 hom., cov: 32)
  • Exomes 𝑓: 0.81 (467556 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.94
• Publications: 44 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 -19 ACMG points.

• 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 vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, Kniest dysplasia, Stickler syndrome type 1, platyspondylic dysplasia, Torrance type, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloperipheral dysplasia, spondyloepiphyseal dysplasia, Stanescu type, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia congenita, multiple epiphyseal dysplasia, Beighton type, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, autosomal dominant rhegmatogenous retinal detachment, spondylometaphyseal dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, familial avascular necrosis of femoral head, dysspondyloenchondromatosis, spondylometaphyseal dysplasia, Schmidt type, hypochondrogenesis, otospondylomegaepiphyseal dysplasia, autosomal recessive, otospondylomegaepiphyseal dysplasia, avascular necrosis of femoral head, primary, 1.
• BP4: Computational evidence support a benign effect (MetaRNN=6.506543E-6).
• BP6: Variant 12-48004297-T-A is Benign according to our data. Variant chr12-48004297-T-A is described in ClinVar as Benign. ClinVar VariationId is 93788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 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.25A>T	p.Thr9Ser	missense	Exon 1 of 54	NP_001835.3
	COL2A1	NM_033150.3		c.25A>T	p.Thr9Ser	missense	Exon 1 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.25A>T	p.Thr9Ser	missense	Exon 1 of 54	ENSP00000369889.3	P02458-2
	COL2A1	ENST00000337299.7	TSL:1	c.25A>T	p.Thr9Ser	missense	Exon 1 of 53	ENSP00000338213.6	P02458-1
	COL2A1	ENST00000928357.1		c.25A>T	p.Thr9Ser	missense	Exon 1 of 54	ENSP00000598416.1

Frequencies

GnomAD3 genomes AF: 0.757 AC: 114999 AN: 151936 Hom.: 44122 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.767

GnomAD2 exomes AF: 0.742 AC: 113435 AN: 152974 AF XY: 0.753

Gnomad AFR exome AF: 0.666

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.790

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.815 AC: 1138155 AN: 1397016 Hom.: 467556 Cov.: 38 AF XY: 0.814 AC XY: 561221 AN XY: 689082

African (AFR) AF: 0.653 AC: 20596 AN: 31538

American (AMR) AF: 0.573 AC: 20436 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 20002 AN: 25158

East Asian (EAS) AF: 0.570 AC: 20361 AN: 35710

South Asian (SAS) AF: 0.765 AC: 60580 AN: 79162

European-Finnish (FIN) AF: 0.757 AC: 36941 AN: 48818

Middle Eastern (MID) AF: 0.829 AC: 4453 AN: 5374

European-Non Finnish (NFE) AF: 0.843 AC: 908686 AN: 1077678

Other (OTH) AF: 0.796 AC: 46100 AN: 57900

GnomAD4 genome AF: 0.757 AC: 115070 AN: 152054 Hom.: 44143 Cov.: 32 AF XY: 0.750 AC XY: 55765 AN XY: 74328

African (AFR) AF: 0.668 AC: 27689 AN: 41462

American (AMR) AF: 0.674 AC: 10318 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2786 AN: 3470

East Asian (EAS) AF: 0.596 AC: 3066 AN: 5140

South Asian (SAS) AF: 0.749 AC: 3616 AN: 4828

European-Finnish (FIN) AF: 0.756 AC: 7996 AN: 10578

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57043 AN: 67954

Other (OTH) AF: 0.764 AC: 1616 AN: 2116

Alfa AF: 0.816 Hom.: 38303

Bravo AF: 0.743

TwinsUK AF: 0.839 AC: 3111

ALSPAC AF: 0.843 AC: 3250

ESP6500AA AF: 0.688 AC: 2615

ESP6500EA AF: 0.843 AC: 6023

ExAC AF: 0.633 AC: 23641

Asia WGS AF: 0.654 AC: 2277 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.085
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0000065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.21
Sift	Benign	0.65	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.079
MPC		0.11
ClinPred		0.0058	T
GERP RS		2.9
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.65
Mutation Taster		=94/6	disease causing (ClinVar)

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: rs3803183; hg19: chr12-48398080; COSMIC: COSV61527604; COSMIC: COSV61527604;