rs139446305

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000089.4(COL1A2):c.1295G>A(p.Arg432Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000468 in 1,603,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R432G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:1

Conservation

PhyloP100: 4.62

Publications

4 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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=0.27593195).

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.1295G>A	p.Arg432Gln	missense	Exon 23 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.1295G>A	p.Arg432Gln	missense	Exon 23 of 52	ENSP00000297268.6	P08123
COL1A2	ENST00000959377.1		c.1295G>A	p.Arg432Gln	missense	Exon 23 of 52	ENSP00000629436.1
COL1A2	ENST00000959379.1		c.1295G>A	p.Arg432Gln	missense	Exon 23 of 52	ENSP00000629438.1

Frequencies

GnomAD3 genomes

AF:

0.000193

AC:

AN:

150426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000590

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000726

AC:

AN:

234146

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.000399

Gnomad AMR exome

AF:

0.0000908

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000479

Gnomad OTH exome

AF:

0.000344

GnomAD4 exome

AF:

0.0000317

AC:

AN:

1453080

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

721974

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33352

American (AMR)

AF:

0.0000458

AC:

AN:

43712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

1107472

Other (OTH)

AF:

0.0000500

AC:

AN:

60042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000193

AC:

AN:

150528

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

AN XY:

73394

show subpopulations

African (AFR)

AF:

0.000588

AC:

AN:

40806

American (AMR)

AF:

0.000133

AC:

AN:

15062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5110

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67816

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

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:

0.0000745

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cardiovascular phenotype (1)

not specified (1)

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

Osteogenesis imperfecta type I;C4303789:Ehlers-Danlos syndrome, cardiac valvular type;CN293783:Ehlers-Danlos syndrome, arthrochalasia type, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

0.64

PhyloP100

4.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.49

Sift

Benign

0.071

Sift4G

Benign

0.079

Polyphen

0.94

Vest4

0.47

MVP

0.85

MPC

0.84

ClinPred

0.036

GERP RS

5.8

Varity_R

0.066

gMVP

0.66

Mutation Taster

=94/6

polymorphism

(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