NM_000089.4:c.3135C>T

Variant names:

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.3135C>T(p.Gly1045Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,190 control chromosomes in the GnomAD database, including 13,529 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. G1045G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1033 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12496 hom. )

Consequence

COL1A2
NM_000089.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.800

Publications

22 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):

COL1A2-related Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
COL1A2-related osteogenesis imperfecta
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Ehlers-Danlos syndrome, arthrochalasia type, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
osteogenesis imperfecta
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
osteogenesis imperfecta type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
osteogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
osteogenesis imperfecta type 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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: Orphanet, Genomics England PanelApp, G2P, ClinGen
combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
Ehlers-Danlos/osteogenesis imperfecta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
high bone mass osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital heart disease
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

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=-0.63).

BP6

Variant 7-94427037-C-T is Benign according to our data. Variant chr7-94427037-C-T is described in ClinVar as Benign. ClinVar VariationId is 254956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A2	NM_000089.4	MANE Select	c.3135C>T	p.Gly1045Gly	synonymous	Exon 47 of 52	NP_000080.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL1A2	ENST00000297268.11	TSL:1 MANE Select	c.3135C>T	p.Gly1045Gly	synonymous	Exon 47 of 52	ENSP00000297268.6	P08123
COL1A2	ENST00000959377.1		c.3132C>T	p.Gly1044Gly	synonymous	Exon 47 of 52	ENSP00000629436.1
COL1A2	ENST00000959379.1		c.3135C>T	p.Gly1045Gly	synonymous	Exon 47 of 52	ENSP00000629438.1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16311

AN:

152024

Hom.:

1032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0578

Gnomad AMI

AF:

0.273

Gnomad AMR

AF:

0.0580

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.113

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.204

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.0752

GnomAD2 exomes

AF:

0.122

AC:

30569

AN:

251082

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.0552

Gnomad AMR exome

AF:

0.0793

Gnomad ASJ exome

AF:

0.0699

Gnomad EAS exome

AF:

0.100

Gnomad FIN exome

AF:

0.196

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.127

AC:

185237

AN:

1461052

Hom.:

12496

Cov.:

AF XY:

0.128

AC XY:

93261

AN XY:

726850

show subpopulations

African (AFR)

AF:

0.0557

AC:

1866

AN:

33476

American (AMR)

AF:

0.0780

AC:

3486

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0712

AC:

1860

AN:

26128

East Asian (EAS)

AF:

0.131

AC:

5211

AN:

39690

South Asian (SAS)

AF:

0.172

AC:

14792

AN:

86226

European-Finnish (FIN)

AF:

0.189

AC:

10098

AN:

53414

Middle Eastern (MID)

AF:

0.0493

AC:

284

AN:

5764

European-Non Finnish (NFE)

AF:

0.127

AC:

140889

AN:

1111270

Other (OTH)

AF:

0.112

AC:

6751

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

8235

16471

24706

32942

41177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5068

10136

15204

20272

25340

<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:

0.107

AC:

16329

AN:

152138

Hom.:

1033

Cov.:

AF XY:

0.109

AC XY:

8117

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0579

AC:

2402

AN:

41516

American (AMR)

AF:

0.0580

AC:

887

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3470

East Asian (EAS)

AF:

0.114

AC:

588

AN:

5180

South Asian (SAS)

AF:

0.176

AC:

846

AN:

4808

European-Finnish (FIN)

AF:

0.204

AC:

2160

AN:

10568

Middle Eastern (MID)

AF:

0.0377

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.129

AC:

8738

AN:

67990

Other (OTH)

AF:

0.0782

AC:

165

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

729

1457

2186

2914

3643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.107

Hom.:

918

Bravo

AF:

0.0936

Asia WGS

AF:

0.151

AC:

523

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.111

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome, arthrochalasia type, 2 (1)

Osteogenesis imperfecta (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.2

(source)

DANN

Benign

0.55

PhyloP100

-0.80

Mutation Taster

=93/7

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over