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rs41317915

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001844.5(COL2A1):​c.1266+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,614,042 control chromosomes in the GnomAD database, including 245 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 25 hom., cov: 32)
Exomes 𝑓: 0.016 ( 220 hom. )

Consequence

COL2A1
NM_001844.5 splice_region, intron

Scores

2
Splicing: ADA: 0.001001
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.612
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 -18 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-47987262-C-T is Benign according to our data. Variant chr12-47987262-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47987262-C-T is described in Lovd as [Benign]. Variant chr12-47987262-C-T is described in Lovd as [Likely_benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0137 (2089/152234) while in subpopulation AMR AF= 0.0201 (307/15300). AF 95% confidence interval is 0.0182. There are 25 homozygotes in gnomad4. There are 1046 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd4 at 2089 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL2A1NM_001844.5 linkuse as main transcriptc.1266+7G>A splice_region_variant, intron_variant ENST00000380518.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL2A1ENST00000380518.8 linkuse as main transcriptc.1266+7G>A splice_region_variant, intron_variant 1 NM_001844.5 P1P02458-2
COL2A1ENST00000337299.7 linkuse as main transcriptc.1059+7G>A splice_region_variant, intron_variant 1 P02458-1
COL2A1ENST00000493991.5 linkuse as main transcriptn.190+7G>A splice_region_variant, intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0137
AC:
2090
AN:
152116
Hom.:
25
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00280
Gnomad AMI
AF:
0.0175
Gnomad AMR
AF:
0.0201
Gnomad ASJ
AF:
0.0256
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.00952
Gnomad FIN
AF:
0.0221
Gnomad MID
AF:
0.0380
Gnomad NFE
AF:
0.0180
Gnomad OTH
AF:
0.0192
GnomAD3 exomes
AF:
0.0136
AC:
3421
AN:
251408
Hom.:
35
AF XY:
0.0142
AC XY:
1934
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00178
Gnomad AMR exome
AF:
0.0120
Gnomad ASJ exome
AF:
0.0191
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00794
Gnomad FIN exome
AF:
0.0180
Gnomad NFE exome
AF:
0.0180
Gnomad OTH exome
AF:
0.0161
GnomAD4 exome
AF:
0.0162
AC:
23752
AN:
1461808
Hom.:
220
Cov.:
33
AF XY:
0.0162
AC XY:
11794
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00197
Gnomad4 AMR exome
AF:
0.0121
Gnomad4 ASJ exome
AF:
0.0206
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00796
Gnomad4 FIN exome
AF:
0.0170
Gnomad4 NFE exome
AF:
0.0179
Gnomad4 OTH exome
AF:
0.0161
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0137
AC:
2089
AN:
152234
Hom.:
25
Cov.:
32
AF XY:
0.0141
AC XY:
1046
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.00279
Gnomad4 AMR
AF:
0.0201
Gnomad4 ASJ
AF:
0.0256
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00952
Gnomad4 FIN
AF:
0.0221
Gnomad4 NFE
AF:
0.0180
Gnomad4 OTH
AF:
0.0190
Alfa
AF:
0.0161
Hom.:
13
Bravo
AF:
0.0131
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.0233
EpiControl
AF:
0.0234

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 18, 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. -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 06, 2023- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsAug 31, 2018- -
Achondrogenesis type II;C0265279:Kniest dysplasia;C0432214:Namaqualand hip dysplasia;C0432221:Spondylometaphyseal dysplasia - Sutcliffe type;C0700635:Spondyloepimetaphyseal dysplasia, Strudwick type;C0796173:Spondyloperipheral dysplasia;C1442965:Legg-Calve-Perthes disease;C1835437:Platyspondylic dysplasia, Torrance type;C1836080:Stickler syndrome, type I, nonsyndromic ocular;C1836683:Spondyloepiphyseal dysplasia with metatarsal shortening;C1851536:Multiple epiphyseal dysplasia, Beighton type;C1852989:Vitreoretinopathy with phalangeal epiphyseal dysplasia;C2020284:Stickler syndrome type 1;C2745959:Spondyloepiphyseal dysplasia congenita;C4225273:Spondyloepiphyseal dysplasia, Stanescu type;C4551562:Avascular necrosis of femoral head, primary, 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsNov 10, 2021- -
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. -
Connective tissue disorder Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 23, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
6.7
DANN
Benign
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0010
dbscSNV1_RF
Benign
0.12
SpliceAI score (max)
0.020
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: rs41317915; hg19: chr12-48381045; API