NM_000089.4:c.2403+186T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000089.4(COL1A2):​c.2403+186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 526,010 control chromosomes in the GnomAD database, including 788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 201 hom., cov: 32)
Exomes 𝑓: 0.049 ( 587 hom. )

Consequence

COL1A2
NM_000089.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.42

Publications

10 publications found
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]
COL1A2 Gene-Disease associations (from GenCC):
  • Ehlers-Danlos syndrome, arthrochalasia type, 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
  • osteogenesis imperfecta
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • osteogenesis imperfecta type 1
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • osteogenesis imperfecta type 2
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
  • osteogenesis imperfecta type 3
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
  • osteogenesis imperfecta type 4
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • Ehlers-Danlos syndrome, arthrochalasia type
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
  • Ehlers-Danlos syndrome, cardiac valvular type
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, PanelApp Australia, Orphanet, G2P
  • combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
  • Ehlers-Danlos/osteogenesis imperfecta syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • high bone mass osteogenesis imperfecta
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 7-94422138-T-C is Benign according to our data. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94422138-T-C is described in CliVar as Benign. Clinvar id is 678459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL1A2NM_000089.4 linkc.2403+186T>C intron_variant Intron 39 of 51 ENST00000297268.11 NP_000080.2 P08123A0A0S2Z3H5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkc.2403+186T>C intron_variant Intron 39 of 51 1 NM_000089.4 ENSP00000297268.6 P08123
COL1A2ENST00000497316.5 linkn.800+186T>C intron_variant Intron 8 of 8 2
COL1A2ENST00000473573.5 linkn.*98T>C downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0434
AC:
6588
AN:
151964
Hom.:
201
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0137
Gnomad AMI
AF:
0.119
Gnomad AMR
AF:
0.0377
Gnomad ASJ
AF:
0.0329
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00933
Gnomad FIN
AF:
0.0465
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0679
Gnomad OTH
AF:
0.0340
GnomAD4 exome
AF:
0.0490
AC:
18313
AN:
373932
Hom.:
587
AF XY:
0.0473
AC XY:
9170
AN XY:
193718
show subpopulations
African (AFR)
AF:
0.0112
AC:
131
AN:
11650
American (AMR)
AF:
0.0351
AC:
571
AN:
16252
Ashkenazi Jewish (ASJ)
AF:
0.0329
AC:
388
AN:
11792
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29762
South Asian (SAS)
AF:
0.0117
AC:
289
AN:
24686
European-Finnish (FIN)
AF:
0.0433
AC:
1141
AN:
26354
Middle Eastern (MID)
AF:
0.00992
AC:
19
AN:
1916
European-Non Finnish (NFE)
AF:
0.0645
AC:
14766
AN:
229098
Other (OTH)
AF:
0.0450
AC:
1008
AN:
22422
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
789
1579
2368
3158
3947
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
72
144
216
288
360
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0433
AC:
6587
AN:
152078
Hom.:
201
Cov.:
32
AF XY:
0.0411
AC XY:
3056
AN XY:
74366
show subpopulations
African (AFR)
AF:
0.0136
AC:
566
AN:
41506
American (AMR)
AF:
0.0376
AC:
574
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.0329
AC:
114
AN:
3470
East Asian (EAS)
AF:
0.000386
AC:
2
AN:
5180
South Asian (SAS)
AF:
0.00934
AC:
45
AN:
4816
European-Finnish (FIN)
AF:
0.0465
AC:
490
AN:
10546
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.0679
AC:
4615
AN:
67972
Other (OTH)
AF:
0.0336
AC:
71
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
308
615
923
1230
1538
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
74
148
222
296
370
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0535
Hom.:
56
Bravo
AF:
0.0419
Asia WGS
AF:
0.00491
AC:
17
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 14, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
6.1
DANN
Benign
0.56
PhyloP100
1.4
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs2472; hg19: chr7-94051450; API