rs28754326

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.936+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,546 control chromosomes in the GnomAD database, including 11,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2022 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9489 hom. )

Consequence

COL1A2
NM_000089.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.656

Publications

5 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

COL1A2 links:

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=-0.8).

BP6

Variant 7-94409654-G-A is Benign according to our data. Variant chr7-94409654-G-A is described in ClinVar as Benign. ClinVar VariationId is 674979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4 link	c.936+46G>A		intron_variant	Intron 18 of 51	ENST00000297268.11	NP_000080.2	P08123A0A0S2Z3H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11 link	c.936+46G>A		intron_variant	Intron 18 of 51	1	NM_000089.4	ENSP00000297268.6		P08123

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22328

AN:

152048

Hom.:

2015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.259

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.0426

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.0776

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.143

GnomAD2 exomes

AF:

0.101

AC:

25408

AN:

251450

AF XY:

0.0967

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.0807

Gnomad ASJ exome

AF:

0.131

Gnomad EAS exome

AF:

0.0362

Gnomad FIN exome

AF:

0.0803

Gnomad NFE exome

AF:

0.114

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.109

AC:

159563

AN:

1461380

Hom.:

9489

Cov.:

AF XY:

0.106

AC XY:

77412

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.260

AC:

8689

AN:

33476

American (AMR)

AF:

0.0859

AC:

3843

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

3360

AN:

26136

East Asian (EAS)

AF:

0.0783

AC:

3109

AN:

39698

South Asian (SAS)

AF:

0.0321

AC:

2771

AN:

86252

European-Finnish (FIN)

AF:

0.0832

AC:

4446

AN:

53418

Middle Eastern (MID)

AF:

0.155

AC:

893

AN:

5766

European-Non Finnish (NFE)

AF:

0.113

AC:

125588

AN:

1111526

Other (OTH)

AF:

0.114

AC:

6864

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

8127

16254

24382

32509

40636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4490

8980

13470

17960

22450

<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:

0.147

AC:

22358

AN:

152166

Hom.:

2022

Cov.:

AF XY:

0.141

AC XY:

10520

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.259

AC:

10739

AN:

41472

American (AMR)

AF:

0.115

AC:

1757

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

484

AN:

3470

East Asian (EAS)

AF:

0.0427

AC:

221

AN:

5170

South Asian (SAS)

AF:

0.0299

AC:

144

AN:

4820

European-Finnish (FIN)

AF:

0.0776

AC:

823

AN:

10606

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.114

AC:

7748

AN:

68022

Other (OTH)

AF:

0.142

AC:

300

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

972

1943

2915

3886

4858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<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:

0.131

Hom.:

2281

Bravo

AF:

0.157

Asia WGS

AF:

0.0520

AC:

181

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

Jun 19, 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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

6.2

(source)

DANN

Benign

0.58

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over