7-94427672-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1PP2BP4_ModerateBP6BS1BS2

The NM_000089.4(COL1A2):c.3313G>A(p.Gly1105Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,106 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 8.14

Publications

7 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 -8 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000089.4

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 osteogenesis imperfecta, osteogenesis imperfecta type 1, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, cardiac valvular type, Ehlers-Danlos syndrome, arthrochalasia type, 2, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, osteogenesis imperfecta type 2, high bone mass osteogenesis imperfecta, Ehlers-Danlos/osteogenesis imperfecta syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.12622899).

BP6

Variant 7-94427672-G-A is Benign according to our data. Variant chr7-94427672-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 360968.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00127 (1857/1461870) while in subpopulation SAS AF = 0.00288 (248/86258). AF 95% confidence interval is 0.00258. There are 5 homozygotes in GnomAdExome4. There are 950 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4 link	c.3313G>A	p.Gly1105Ser	missense_variant	Exon 49 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.3313G>A	p.Gly1105Ser	missense_variant	Exon 49 of 52	1	NM_000089.4	ENSP00000297268.6		P08123

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

109

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000995

AC:

250

AN:

251270

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000784

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00127

AC:

1857

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

950

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.00190

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000705

AC:

AN:

39696

South Asian (SAS)

AF:

0.00288

AC:

248

AN:

86258

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00125

AC:

1392

AN:

1111994

Other (OTH)

AF:

0.00139

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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:

0.000716

AC:

109

AN:

152236

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41530

American (AMR)

AF:

0.00183

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000956

Hom.:

Bravo

AF:

0.000899

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000972

AC:

118

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL1A2 c.3313G>A; p.Gly1105Ser variant (rs139851311; ClinVar Variation ID: 360968) is reported in the literature in several individuals affected with osteogenesis imperfecta or Ehlers-Danlos Syndrome, though it was not demonstrated to cause disease (Junkiert-Czarnecka 2022, Lin 2024, Mei 2022, Stephen 2014, Zhang 2012). This variant is found in the South Asian population with an overall allele frequency of 0.24% (73/30610 alleles) in the Genome Aggregation Database (v2.1.1). The glycine at codon 1105 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.783). It is unclear if this glycine residue is incorporated into the collagen triple helix domain. While the population frequency of this variant is inconsistent with disease, given the lack of clinical and functional data, the significance of the p.Gly1105Ser variant is uncertain at this time. References: Junkiert-Czarnecka A et al. Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome. Curr Issues Mol Biol. 2022 Mar 25;44(4):1472-1478. PMID: 35723357. Lin X et al. Genotype-phenotype relationship and comparison between eastern and western patients with osteogenesis imperfecta. J Endocrinol Invest. 2024 Jan;47(1):67-77. PMID: 37270749. Mei Y et al. Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. PMID: 35909573. Stephen J et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. Am J Med Genet A. 2014 Jun;164A(6):1482-9. PMID: 24668929. Zhang ZL et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J Bone Miner Metab. 2012 Jan;30(1):69-77. PMID: 21667357. -

Mar 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL1A2: BS1 -

not specified

Benign:2

Oct 23, 2017

GeneDx

Significance:Likely 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. -

Sep 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL1A2 c.3313G>A (p.Gly1105Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 251270 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 85.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Osteogenesis Imperfecta phenotype (2.8e-05). c.3313G>A has been reported in the literature in heterozygous individuals affected with Osteogenesis Imperfecta (Mrosk_2018, Zhang_2012). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (COL1A1 c.2299G>A , p.Gly767Ser), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 360968). Based on the evidence outlined above, the variant was classified as likely benign. -

Osteogenesis imperfecta

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Uncertain:1

Feb 10, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type, 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 05, 2020

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

AlphaMissense

Benign

0.089

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Uncertain

0.66

D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.13

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

8.1

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.4

D;.

REVEL

Pathogenic

0.78

Sift

Benign

0.18

T;.

Sift4G

Benign

0.17

T;T

Polyphen

1.0

D;.

Vest4

0.87

MVP

0.95

MPC

0.21

ClinPred

0.048

GERP RS

5.8

Varity_R

0.72

gMVP

0.91

Mutation Taster

=0/100

disease causing

(source)

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

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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