chr12-47984112-C-T

Variant names:

• chr12-47984112-C-T
• rs1057518908
• NM_001844.5:c.1916G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001844.5(COL2A1):​c.1916G>A​(p.Gly639Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 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, 0.994
• PP5: Variant 12-47984112-C-T is Pathogenic according to our data. Variant chr12-47984112-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.1916G>A	p.Gly639Asp	missense_variant	Exon 29 of 54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.1916G>A	p.Gly639Asp	missense_variant	Exon 29 of 54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.1709G>A	p.Gly570Asp	missense_variant	Exon 28 of 53	1		ENSP00000338213.6
COL2A1	ENST00000493991.5	n.840G>A		non_coding_transcript_exon_variant	Exon 12 of 37	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 14, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple epiphyseal dysplasia;C0036439:Scoliosis;C0349588:Short stature;C1384666:Hearing impairment;C1846442:Hypoplastic acetabulae;C4551649:Developmental dysplasia of the hip Pathogenic:1

Apr 07, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.84	P;P
Vest4		0.98
MutPred		0.99		Gain of solvent accessibility (P = 0.0638);.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		1.0

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: rs1057518908; hg19: chr12-48377895;