rs412777

Positions:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 254952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94412625-A-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
COL1A2	NM_000089.4 linkuse as main transcript	c.1446A>C	p.Pro482Pro	synonymous_variant	25/52	ENST00000297268.11	NP_000080.2	P08123A0A0S2Z3H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A2	ENST00000297268.11 linkuse as main transcript	c.1446A>C	p.Pro482Pro	synonymous_variant	25/52	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

GnomAD3 exomes

AF:

0.339

AC:

84941

AN:

250452

Hom.:

14823

AF XY:

0.341

AC XY:

46165

AN XY:

135476

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 SAS exome

AF:

0.292

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

Gnomad4 AFR exome

AF:

0.344

Gnomad4 AMR exome

AF:

0.249

Gnomad4 ASJ exome

AF:

0.354

Gnomad4 EAS exome

AF:

0.343

Gnomad4 SAS exome

AF:

0.288

Gnomad4 FIN exome

AF:

0.403

Gnomad4 NFE exome

AF:

0.363

Gnomad4 OTH exome

AF:

0.351

GnomAD4 genome

AF:

0.354

AC:

53826

AN:

151916

Hom.:

9610

Cov.:

AF XY:

0.353

AC XY:

26193

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.352

Gnomad4 AMR

AF:

0.311

Gnomad4 ASJ

AF:

0.364

Gnomad4 EAS

AF:

0.308

Gnomad4 SAS

AF:

0.283

Gnomad4 FIN

AF:

0.408

Gnomad4 NFE

AF:

0.366

Gnomad4 OTH

AF:

0.335

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

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ehlers-danlos syndrome, arthrochalasia type, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 III

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Osteogenesis imperfecta with normal sclerae, dominant form

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Osteogenesis imperfecta, perinatal lethal

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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

DANN

Benign

0.65

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over