chr7-94426022-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000089.4(COL1A2):c.2968G>T(p.Ala990Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000998 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A990D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.02

Publications

0 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
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
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: ClinGen, Orphanet
osteogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet
osteogenesis imperfecta type 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
osteogenesis imperfecta type 4
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Ehlers-Danlos syndrome, cardiac valvular type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Orphanet, G2P, ClinGen
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
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 1 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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=0.18483126).

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.2968G>T	p.Ala990Ser	missense	Exon 45 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.2968G>T	p.Ala990Ser	missense	Exon 45 of 52	ENSP00000297268.6	P08123
COL1A2	ENST00000959377.1		c.2965G>T	p.Ala989Ser	missense	Exon 45 of 52	ENSP00000629436.1
COL1A2	ENST00000959379.1		c.2968G>T	p.Ala990Ser	missense	Exon 45 of 52	ENSP00000629438.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251398

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000125

AC:

139

AN:

1111992

Other (OTH)

AF:

0.000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.000113

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.0

PhyloP100

2.0

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.28

REVEL

Benign

0.21

Sift

Benign

0.86

Sift4G

Benign

0.46

Polyphen

0.030

Vest4

0.23

MVP

0.59

MPC

0.19

ClinPred

0.016

GERP RS

1.2

Varity_R

0.014

gMVP

0.43

Mutation Taster

=91/9

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