rs41317939

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000380518.8(COL2A1):ā€‹c.1836T>Cā€‹(p.Gly612=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,613,810 control chromosomes in the GnomAD database, including 3,806 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.049 ( 246 hom., cov: 33)
Exomes š‘“: 0.065 ( 3560 hom. )

Consequence

COL2A1
ENST00000380518.8 splice_region, synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 12-47984597-A-G is Benign according to our data. Variant chr12-47984597-A-G is described in ClinVar as [Benign]. Clinvar id is 258217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47984597-A-G is described in Lovd as [Benign]. Variant chr12-47984597-A-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-1.04 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL2A1NM_001844.5 linkuse as main transcriptc.1836T>C p.Gly612= splice_region_variant, synonymous_variant 28/54 ENST00000380518.8 NP_001835.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL2A1ENST00000380518.8 linkuse as main transcriptc.1836T>C p.Gly612= splice_region_variant, synonymous_variant 28/541 NM_001844.5 ENSP00000369889 P1P02458-2
COL2A1ENST00000337299.7 linkuse as main transcriptc.1629T>C p.Gly543= splice_region_variant, synonymous_variant 27/531 ENSP00000338213 P02458-1
COL2A1ENST00000493991.5 linkuse as main transcriptn.760T>C splice_region_variant, non_coding_transcript_exon_variant 11/372

Frequencies

GnomAD3 genomes
AF:
0.0493
AC:
7504
AN:
152192
Hom.:
246
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0207
Gnomad AMI
AF:
0.0241
Gnomad AMR
AF:
0.0289
Gnomad ASJ
AF:
0.0115
Gnomad EAS
AF:
0.000770
Gnomad SAS
AF:
0.0130
Gnomad FIN
AF:
0.0862
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0745
Gnomad OTH
AF:
0.0444
GnomAD3 exomes
AF:
0.0477
AC:
11965
AN:
250704
Hom.:
437
AF XY:
0.0474
AC XY:
6424
AN XY:
135614
show subpopulations
Gnomad AFR exome
AF:
0.0179
Gnomad AMR exome
AF:
0.0189
Gnomad ASJ exome
AF:
0.0123
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0115
Gnomad FIN exome
AF:
0.0873
Gnomad NFE exome
AF:
0.0738
Gnomad OTH exome
AF:
0.0496
GnomAD4 exome
AF:
0.0646
AC:
94408
AN:
1461500
Hom.:
3560
Cov.:
33
AF XY:
0.0630
AC XY:
45834
AN XY:
727066
show subpopulations
Gnomad4 AFR exome
AF:
0.0174
Gnomad4 AMR exome
AF:
0.0207
Gnomad4 ASJ exome
AF:
0.0131
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.0115
Gnomad4 FIN exome
AF:
0.0874
Gnomad4 NFE exome
AF:
0.0751
Gnomad4 OTH exome
AF:
0.0550
GnomAD4 genome
AF:
0.0493
AC:
7509
AN:
152310
Hom.:
246
Cov.:
33
AF XY:
0.0490
AC XY:
3646
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0208
Gnomad4 AMR
AF:
0.0289
Gnomad4 ASJ
AF:
0.0115
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.0133
Gnomad4 FIN
AF:
0.0862
Gnomad4 NFE
AF:
0.0744
Gnomad4 OTH
AF:
0.0440
Alfa
AF:
0.0599
Hom.:
173
Bravo
AF:
0.0422
Asia WGS
AF:
0.0120
AC:
43
AN:
3478
EpiCase
AF:
0.0599
EpiControl
AF:
0.0633

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 08, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 09, 2023- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Stickler syndrome type 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Type II Collagenopathies Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
0.021
DANN
Benign
0.57

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41317939; hg19: chr12-48378380; COSMIC: COSV61530805; COSMIC: COSV61530805; API