12-47996607-C-A

Variant names:

• chr12-47996607-C-A
• rs201817670
• NM_001844.5:c.550G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PP2 BP4_Moderate BP6_Moderate BS2

The NM_001844.5(COL2A1):​c.550G>T​(p.Ala184Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.64

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 Likely_benign. Variant got -5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.111219674).
• BP6: Variant 12-47996607-C-A is Benign according to our data. Variant chr12-47996607-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2162631.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL2A1	NM_001844.5	c.550G>T	p.Ala184Ser	missense_variant	Exon 8 of 54	ENST00000380518.8	NP_001835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL2A1	ENST00000380518.8	c.550G>T	p.Ala184Ser	missense_variant	Exon 8 of 54	1	NM_001844.5	ENSP00000369889.3
COL2A1	ENST00000337299.7	c.343G>T	p.Ala115Ser	missense_variant	Exon 7 of 53	1		ENSP00000338213.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251452 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.27	N;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.22
Sift	Benign	0.51	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0060	B;B
Vest4		0.28
MVP		0.53
MPC		0.69
ClinPred		0.15	T
GERP RS		3.9
Varity_R		0.049
gMVP		0.33

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: rs201817670; hg19: chr12-48390390;