rs138498898

chr12-47974258-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001844.5(COL2A1):c.4148C>T(p.Thr1383Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1383T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:1
• Conservation: PhyloP100: 0.876

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 -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL2A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.37494895).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.4148C>T	p.Thr1383Met	missense_variant	53/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.4148C>T	p.Thr1383Met	missense_variant	53/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.3941C>T	p.Thr1314Met	missense_variant	52/53	1
COL2A1	ENST00000493991.5	n.3234C>T		non_coding_transcript_exon_variant	36/37	2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251458 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461880 Hom.: 0 Cov.: 35 AF XY: 0.0000743 AC XY: 54 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000507 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	Identified in a patient with hip pain and avascular necrosis of the femoral head whose niece had a history of epiphyseal dysplasia but did not harbor any variants in the COL2A1 gene (Kannu et al., 2011); also identified in a patient with early-onset bilateral sensorineural hearing loss (Miyagawa et al., 2013); Identified independently and in conjunction with additional variants in individuals referred for connective tissue disorder genetic testing at GeneDx; segregation data is limited or absent at this time; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 23967202, 21671384, 27183340, 30328481) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2022	- -

Avascular necrosis of femoral head, primary, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2011	- -

COL2A1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The COL2A1 c.4148C>T variant is predicted to result in the amino acid substitution p.Thr1383Met. This variant has been reported in the heterozygous state in an individual with avascular necrosis of the femur head (Kannu et al. 2011. PubMed ID: 21671384) and in an individual with deafness (Table S2, Miyagawa et al. 2013. PubMed ID: 23967202). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has classifications ranging from Likely Benign to Likely Pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/29637/). At this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.44	B;B
Vest4		0.80
MVP		0.86
MPC		0.33
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.61
gMVP		0.77

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: rs138498898; hg19: chr12-48368041;