rs1179925303

Positions:

• chr12-47982567-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_001844.5(COL2A1):​c.2236C>T​(p.Pro746Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,502 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

LOC105369752 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001844.5
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL2A1. . Gene score misZ 3.2926 (greater than the threshold 3.09). Trascript score misZ 5.3726 (greater than threshold 3.09). GenCC has associacion of gene with spondylometaphyseal dysplasia, Schmidt type, spondyloepiphyseal dysplasia congenita, hypochondrogenesis, autosomal dominant rhegmatogenous retinal detachment, spondyloperipheral dysplasia, Kniest dysplasia, familial avascular necrosis of femoral head, spondylometaphyseal dysplasia, mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis, otospondylomegaepiphyseal dysplasia, autosomal recessive, multiple epiphyseal dysplasia, Beighton type, otospondylomegaepiphyseal dysplasia, Legg-Calve-Perthes disease, achondrogenesis type II, spondyloepiphyseal dysplasia, Stanescu type, platyspondylic dysplasia, Torrance type, Stickler syndrome type 1, dysspondyloenchondromatosis, vitreoretinopathy with phalangeal epiphyseal dysplasia, Stickler syndrome, type I, nonsyndromic ocular, avascular necrosis of femoral head, primary, 1, spondyloepiphyseal dysplasia with metatarsal shortening, spondyloepimetaphyseal dysplasia, Strudwick type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.2236C>T	p.Pro746Ser	missense_variant	34/54	ENST00000380518.8
LOC105369752	XR_944910.2	n.278+93G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.2236C>T	p.Pro746Ser	missense_variant	34/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.2029C>T	p.Pro677Ser	missense_variant	33/53	1
COL2A1	ENST00000483376.1	n.414C>T		non_coding_transcript_exon_variant	5/8	5
COL2A1	ENST00000493991.5	n.1160C>T		non_coding_transcript_exon_variant	17/37	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248268 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134600

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461502 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.64
Sift	Benign	0.21	T;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.40		Loss of catalytic residue at P745 (P = 0.0131);.;
MVP		0.75
MPC		1.8
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1179925303; hg19: chr12-48376350;