chr7-94429325-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000089.4(COL1A2):​c.3849T>C​(p.Thr1283Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,614,156 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 31)
Exomes 𝑓: 0.00037 ( 5 hom. )

Consequence

COL1A2
NM_000089.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.626

Publications

1 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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 7-94429325-T-C is Benign according to our data. Variant chr7-94429325-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.626 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (508/152308) while in subpopulation AFR AF = 0.0112 (466/41568). AF 95% confidence interval is 0.0104. There are 3 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL1A2NM_000089.4 linkc.3849T>C p.Thr1283Thr synonymous_variant Exon 51 of 52 ENST00000297268.11 NP_000080.2 P08123A0A0S2Z3H5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkc.3849T>C p.Thr1283Thr synonymous_variant Exon 51 of 52 1 NM_000089.4 ENSP00000297268.6 P08123
COL1A2ENST00000464916.1 linkn.897T>C non_coding_transcript_exon_variant Exon 3 of 4 2
COL1A2ENST00000481570.5 linkn.4630T>C non_coding_transcript_exon_variant Exon 8 of 8 2

Frequencies

GnomAD3 genomes
AF:
0.00333
AC:
507
AN:
152190
Hom.:
3
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0112
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.000892
AC:
224
AN:
251056
AF XY:
0.000619
show subpopulations
Gnomad AFR exome
AF:
0.0124
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000617
Gnomad OTH exome
AF:
0.000817
GnomAD4 exome
AF:
0.000373
AC:
545
AN:
1461848
Hom.:
5
Cov.:
33
AF XY:
0.000341
AC XY:
248
AN XY:
727222
show subpopulations
African (AFR)
AF:
0.0122
AC:
409
AN:
33478
American (AMR)
AF:
0.000447
AC:
20
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39688
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00225
AC:
13
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000351
AC:
39
AN:
1111994
Other (OTH)
AF:
0.00101
AC:
61
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
33
66
99
132
165
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.00334
AC:
508
AN:
152308
Hom.:
3
Cov.:
31
AF XY:
0.00298
AC XY:
222
AN XY:
74482
show subpopulations
African (AFR)
AF:
0.0112
AC:
466
AN:
41568
American (AMR)
AF:
0.00183
AC:
28
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68028
Other (OTH)
AF:
0.00236
AC:
5
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
23
45
68
90
113
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00153
Hom.:
1
Bravo
AF:
0.00368
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Feb 12, 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. -

Dec 06, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 06, 2024
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:3
Jan 16, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

May 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

COL1A2: BP4, BP7, BS1, BS2 -

Osteogenesis imperfecta Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Dec 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type, 2 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Jul 19, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.63
CADD
Benign
3.1
DANN
Benign
0.72
PhyloP100
-0.63
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: rs34038163; hg19: chr7-94058637; API