rs186233557

chr12-47985759-C-Achr12-47985759-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 6P and 13B. PM1 PM5 PP2 PP3 BP4_Strong BP6 BS1 BS2

The NM_001844.5(COL2A1):c.1649G>T(p.Arg550Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000304 in 1,613,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R550C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: COL2A1 NM_001844.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 6.16

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 Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001844.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-47985760-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, COL2A1
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.022258788).
• BP6: Variant 12-47985759-C-A is Benign according to our data. Variant chr12-47985759-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258213.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000847 (129/152282) while in subpopulation AMR AF= 0.00777 (119/15306). AF 95% confidence interval is 0.00664. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL2A1	NM_001844.5	c.1649G>T	p.Arg550Leu	missense_variant	25/54	ENST00000380518.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL2A1	ENST00000380518.8	c.1649G>T	p.Arg550Leu	missense_variant	25/54	1	NM_001844.5	P1
COL2A1	ENST00000337299.7	c.1442G>T	p.Arg481Leu	missense_variant	24/53	1
COL2A1	ENST00000493991.5	n.573G>T		non_coding_transcript_exon_variant	8/37	2

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00116 AC: 291 AN: 249912 Hom.: 0 AF XY: 0.000858 AC XY: 116 AN XY: 135252

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00818

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1461606 Hom.: 1 Cov.: 34 AF XY: 0.000201 AC XY: 146 AN XY: 727098

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00750

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74460

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00777

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000539 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000906 AC: 110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	This variant is associated with the following publications: (PMID: 24664531) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -

Orofacial cleft 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Grupo de Genetica Humana, Facultad de Medicina - Universidad de La Sabana

Nov 22, 2022

Likely pathogenic VUS in the COL2A1 gene, which has been implicated in Stickler syndrome, a condition with manifestations in the eye, ear, joints, face, and palate, including cleft palate. -

Stickler syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	0.84	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.95	P;D
Vest4		0.75
MVP		0.93
MPC		1.3
ClinPred		0.071	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.56
gMVP		0.87

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: rs186233557; hg19: chr12-48379542;