rs17801742

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001844.5(COL2A1):​c.2094+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,613,540 control chromosomes in the GnomAD database, including 3,471 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 232 hom., cov: 33)
Exomes 𝑓: 0.062 ( 3239 hom. )

Consequence

COL2A1
NM_001844.5 splice_region, intron

Scores

2
Splicing: ADA: 0.00008144
2

Clinical Significance

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

Conservation

PhyloP100: -0.570
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.71).
BP6
Variant 12-47983086-T-C is Benign according to our data. Variant chr12-47983086-T-C is described in ClinVar as [Benign]. Clinvar id is 258223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47983086-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL2A1NM_001844.5 linkuse as main transcriptc.2094+7A>G splice_region_variant, intron_variant ENST00000380518.8 NP_001835.3 P02458-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL2A1ENST00000380518.8 linkuse as main transcriptc.2094+7A>G splice_region_variant, intron_variant 1 NM_001844.5 ENSP00000369889.3 P02458-2
COL2A1ENST00000337299.7 linkuse as main transcriptc.1887+7A>G splice_region_variant, intron_variant 1 ENSP00000338213.6 P02458-1
COL2A1ENST00000483376.1 linkuse as main transcriptn.272+7A>G splice_region_variant, intron_variant 5
COL2A1ENST00000493991.5 linkuse as main transcriptn.1018+7A>G splice_region_variant, intron_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0497
AC:
7558
AN:
152012
Hom.:
233
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0292
Gnomad AMI
AF:
0.0154
Gnomad AMR
AF:
0.0293
Gnomad ASJ
AF:
0.0167
Gnomad EAS
AF:
0.000772
Gnomad SAS
AF:
0.0119
Gnomad FIN
AF:
0.0772
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0714
Gnomad OTH
AF:
0.0459
GnomAD3 exomes
AF:
0.0454
AC:
11332
AN:
249550
Hom.:
361
AF XY:
0.0450
AC XY:
6081
AN XY:
135036
show subpopulations
Gnomad AFR exome
AF:
0.0274
Gnomad AMR exome
AF:
0.0201
Gnomad ASJ exome
AF:
0.0168
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0109
Gnomad FIN exome
AF:
0.0753
Gnomad NFE exome
AF:
0.0693
Gnomad OTH exome
AF:
0.0469
GnomAD4 exome
AF:
0.0622
AC:
90930
AN:
1461410
Hom.:
3239
Cov.:
34
AF XY:
0.0607
AC XY:
44125
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.0263
Gnomad4 AMR exome
AF:
0.0218
Gnomad4 ASJ exome
AF:
0.0172
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.0108
Gnomad4 FIN exome
AF:
0.0760
Gnomad4 NFE exome
AF:
0.0722
Gnomad4 OTH exome
AF:
0.0535
GnomAD4 genome
AF:
0.0497
AC:
7559
AN:
152130
Hom.:
232
Cov.:
33
AF XY:
0.0492
AC XY:
3659
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0293
Gnomad4 AMR
AF:
0.0292
Gnomad4 ASJ
AF:
0.0167
Gnomad4 EAS
AF:
0.000773
Gnomad4 SAS
AF:
0.0121
Gnomad4 FIN
AF:
0.0772
Gnomad4 NFE
AF:
0.0713
Gnomad4 OTH
AF:
0.0454
Alfa
AF:
0.0577
Hom.:
387
Bravo
AF:
0.0441
Asia WGS
AF:
0.0140
AC:
48
AN:
3478
EpiCase
AF:
0.0564
EpiControl
AF:
0.0614

ClinVar

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

Submissions by phenotype

not specified Benign:5
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, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
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- -
Stickler syndrome type 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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 12, 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
-0.71
CADD
Benign
8.0
DANN
Benign
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000081
dbscSNV1_RF
Benign
0.0
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: rs17801742; hg19: chr12-48376869; API