GeneBe

rs421587

Positions:

Variant summary

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

The NM_000089.4(COL1A2):​c.1665+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,605,380 control chromosomes in the GnomAD database, including 71,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6230 hom., cov: 32)
Exomes 𝑓: 0.30 ( 65410 hom. )

Consequence

COL1A2
NM_000089.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.368
Variant links:
Genes affected
COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 7-94413962-A-G is Benign according to our data. Variant chr7-94413962-A-G is described in ClinVar as [Benign]. Clinvar id is 254954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94413962-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A2NM_000089.4 linkuse as main transcriptc.1665+15A>G intron_variant ENST00000297268.11 NP_000080.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkuse as main transcriptc.1665+15A>G intron_variant 1 NM_000089.4 ENSP00000297268 P1
COL1A2ENST00000488298.5 linkuse as main transcriptn.89+15A>G intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.284
AC:
43118
AN:
151852
Hom.:
6219
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.262
Gnomad AMI
AF:
0.392
Gnomad AMR
AF:
0.235
Gnomad ASJ
AF:
0.262
Gnomad EAS
AF:
0.169
Gnomad SAS
AF:
0.237
Gnomad FIN
AF:
0.348
Gnomad MID
AF:
0.236
Gnomad NFE
AF:
0.311
Gnomad OTH
AF:
0.260
GnomAD3 exomes
AF:
0.273
AC:
68577
AN:
250816
Hom.:
9786
AF XY:
0.273
AC XY:
36986
AN XY:
135516
show subpopulations
Gnomad AFR exome
AF:
0.260
Gnomad AMR exome
AF:
0.241
Gnomad ASJ exome
AF:
0.250
Gnomad EAS exome
AF:
0.144
Gnomad SAS exome
AF:
0.231
Gnomad FIN exome
AF:
0.340
Gnomad NFE exome
AF:
0.307
Gnomad OTH exome
AF:
0.275
GnomAD4 exome
AF:
0.297
AC:
432155
AN:
1453410
Hom.:
65410
Cov.:
33
AF XY:
0.296
AC XY:
214002
AN XY:
723568
show subpopulations
Gnomad4 AFR exome
AF:
0.254
Gnomad4 AMR exome
AF:
0.244
Gnomad4 ASJ exome
AF:
0.249
Gnomad4 EAS exome
AF:
0.215
Gnomad4 SAS exome
AF:
0.231
Gnomad4 FIN exome
AF:
0.338
Gnomad4 NFE exome
AF:
0.309
Gnomad4 OTH exome
AF:
0.277
GnomAD4 genome
AF:
0.284
AC:
43165
AN:
151970
Hom.:
6230
Cov.:
32
AF XY:
0.281
AC XY:
20870
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.262
Gnomad4 AMR
AF:
0.235
Gnomad4 ASJ
AF:
0.262
Gnomad4 EAS
AF:
0.169
Gnomad4 SAS
AF:
0.237
Gnomad4 FIN
AF:
0.348
Gnomad4 NFE
AF:
0.311
Gnomad4 OTH
AF:
0.261
Alfa
AF:
0.302
Hom.:
15095
Bravo
AF:
0.277
Asia WGS
AF:
0.218
AC:
758
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 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-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Osteogenesis imperfecta 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. -
Ehlers-danlos syndrome, arthrochalasia type, 2 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. -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
5.8
DANN
Benign
0.47

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: rs421587; hg19: chr7-94043274; COSMIC: COSV51952568; COSMIC: COSV51952568; API