rs412777

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000089.4(COL1A2):c.1446A>C(p.Pro482Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,613,478 control chromosomes in the GnomAD database, including 102,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P482P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.35 ( 9610 hom., cov: 31)

Exomes 𝑓: 0.35 ( 92959 hom. )

Consequence

COL1A2
NM_000089.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.132

Publications

43 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 7-94412625-A-C is Benign according to our data. Variant chr7-94412625-A-C is described in ClinVar as Benign. ClinVar VariationId is 254952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.132 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4 link	c.1446A>C	p.Pro482Pro	synonymous_variant	Exon 25 of 52	ENST00000297268.11	NP_000080.2	P08123A0A0S2Z3H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11 link	c.1446A>C	p.Pro482Pro	synonymous_variant	Exon 25 of 52	1	NM_000089.4	ENSP00000297268.6		P08123

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53810

AN:

151798

Hom.:

9605

Cov.:

show subpopulations

Gnomad AFR

AF:

0.352

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.312

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.408

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.339

GnomAD2 exomes

AF:

0.339

AC:

84941

AN:

250452

AF XY:

0.341

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.240

Gnomad ASJ exome

AF:

0.361

Gnomad EAS exome

AF:

0.312

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.369

Gnomad OTH exome

AF:

0.344

GnomAD4 exome

AF:

0.355

AC:

518539

AN:

1461562

Hom.:

92959

Cov.:

AF XY:

0.354

AC XY:

257137

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.344

AC:

11505

AN:

33478

American (AMR)

AF:

0.249

AC:

11121

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

9262

AN:

26132

East Asian (EAS)

AF:

0.343

AC:

13606

AN:

39690

South Asian (SAS)

AF:

0.288

AC:

24796

AN:

86230

European-Finnish (FIN)

AF:

0.403

AC:

21538

AN:

53388

Middle Eastern (MID)

AF:

0.336

AC:

1938

AN:

5768

European-Non Finnish (NFE)

AF:

0.363

AC:

403610

AN:

1111790

Other (OTH)

AF:

0.351

AC:

21163

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

18362

36724

55085

73447

91809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12628

25256

37884

50512

63140

<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:

0.354

AC:

53826

AN:

151916

Hom.:

9610

Cov.:

AF XY:

0.353

AC XY:

26193

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.352

AC:

14568

AN:

41418

American (AMR)

AF:

0.311

AC:

4756

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1261

AN:

3468

East Asian (EAS)

AF:

0.308

AC:

1583

AN:

5144

South Asian (SAS)

AF:

0.283

AC:

1361

AN:

4812

European-Finnish (FIN)

AF:

0.408

AC:

4295

AN:

10520

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.366

AC:

24879

AN:

67958

Other (OTH)

AF:

0.335

AC:

707

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1819

3637

5456

7274

9093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<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:

0.321

Hom.:

2379

Bravo

AF:

0.347

Asia WGS

AF:

0.282

AC:

980

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 03, 2016

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. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type, 2

Benign:2

Jan 12, 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. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Osteogenesis imperfecta type III

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta with normal sclerae, dominant form

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Osteogenesis imperfecta, perinatal lethal

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 04, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

-0.67

CADD

Benign

5.4

(source)

DANN

Benign

0.65

PhyloP100

-0.13

Mutation Taster

=99/1

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