7-94413927-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000089.4(COL1A2):c.1645C>G(p.Pro549Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,612,780 control chromosomes in the GnomAD database, including 473,323 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49069 hom., cov: 32)

Exomes 𝑓: 0.76 ( 424254 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 2.38

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 -19 ACMG points.

PP2

Missense variant in the COL1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 437 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 2.1491 (below the threshold of 3.09). Trascript score misZ: 3.5344 (above the threshold of 3.09). GenCC associations: The gene is linked to Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, cardiac valvular type, ehlers-danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, high bone mass osteogenesis imperfecta, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, osteogenesis imperfecta type 4, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.

BP4

Computational evidence support a benign effect (MetaRNN=9.558573E-6).

BP6

Variant 7-94413927-C-G is Benign according to our data. Variant chr7-94413927-C-G is described in ClinVar as [Benign]. Clinvar id is 254953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94413927-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4 link	c.1645C>G	p.Pro549Ala	missense_variant	Exon 28 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.1645C>G	p.Pro549Ala	missense_variant	Exon 28 of 52	1	NM_000089.4	ENSP00000297268.6		P08123
COL1A2	ENST00000488298.5 link	n.69C>G		non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.799

AC:

121542

AN:

152032

Hom.:

49013

Cov.:

show subpopulations

Gnomad AFR

AF:

0.888

Gnomad AMI

AF:

0.700

Gnomad AMR

AF:

0.801

Gnomad ASJ

AF:

0.671

Gnomad EAS

AF:

0.916

Gnomad SAS

AF:

0.658

Gnomad FIN

AF:

0.782

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.759

Gnomad OTH

AF:

0.757

GnomAD3 exomes

AF:

0.772

AC:

194105

AN:

251322

Hom.:

75774

AF XY:

0.759

AC XY:

103122

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.892

Gnomad AMR exome

AF:

0.834

Gnomad ASJ exome

AF:

0.680

Gnomad EAS exome

AF:

0.909

Gnomad SAS exome

AF:

0.647

Gnomad FIN exome

AF:

0.787

Gnomad NFE exome

AF:

0.755

Gnomad OTH exome

AF:

0.739

GnomAD4 exome

AF:

0.760

AC:

1110177

AN:

1460630

Hom.:

424254

Cov.:

AF XY:

0.755

AC XY:

548909

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.887

Gnomad4 AMR exome

AF:

0.830

Gnomad4 ASJ exome

AF:

0.676

Gnomad4 EAS exome

AF:

0.938

Gnomad4 SAS exome

AF:

0.644

Gnomad4 FIN exome

AF:

0.783

Gnomad4 NFE exome

AF:

0.758

Gnomad4 OTH exome

AF:

0.749

GnomAD4 genome

AF:

0.800

AC:

121658

AN:

152150

Hom.:

49069

Cov.:

AF XY:

0.797

AC XY:

59315

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.888

Gnomad4 AMR

AF:

0.801

Gnomad4 ASJ

AF:

0.671

Gnomad4 EAS

AF:

0.916

Gnomad4 SAS

AF:

0.659

Gnomad4 FIN

AF:

0.782

Gnomad4 NFE

AF:

0.759

Gnomad4 OTH

AF:

0.759

Alfa

AF:

0.753

Hom.:

29772

Bravo

AF:

0.809

TwinsUK

AF:

0.754

AC:

2795

ALSPAC

AF:

0.759

AC:

2925

ESP6500AA

AF:

0.883

AC:

3891

ESP6500EA

AF:

0.749

AC:

6440

ExAC

AF:

0.769

AC:

93397

EpiCase

AF:

0.742

EpiControl

AF:

0.744

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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. -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Osteogenesis imperfecta

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type, 2

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Ehlers-Danlos syndrome

Benign:1

Jul 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

- -

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

- -

Ehlers-Danlos syndrome, classic type

Benign:1

May 28, 2019

Mendelics

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

AlphaMissense

Benign

0.030

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.36

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.0000096

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.71

N;.

REVEL

Benign

0.29

Sift

Benign

0.98

T;.

Sift4G

Benign

0.66

T;T

Polyphen

0.0

B;.

Vest4

0.099

MPC

0.20

ClinPred

0.0073

GERP RS

5.7

Varity_R

0.025

gMVP

0.36

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