rs121912903

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5

The NM_000089.4(COL1A2):c.1936G>T(p.Gly646Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G646V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COL1A2
NM_000089.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.55

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):

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: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-94417797-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 7-94417796-G-T is Pathogenic according to our data. Variant chr7-94417796-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 17243.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A2	NM_000089.4 link	c.1936G>T	p.Gly646Cys	missense_variant	Exon 32 of 52	ENST00000297268.11	NP_000080.2	P08123A0A0S2Z3H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL1A2	ENST00000297268.11 link	c.1936G>T	p.Gly646Cys	missense_variant	Exon 32 of 52	1	NM_000089.4	ENSP00000297268.6	P08123
COL1A2	ENST00000461525.5 link	n.25G>T		non_coding_transcript_exon_variant	Exon 1 of 7	1
COL1A2	ENST00000473573.5 link	n.273G>T		non_coding_transcript_exon_variant	Exon 4 of 11	2
COL1A2	ENST00000497316.5 link	n.333G>T		non_coding_transcript_exon_variant	Exon 1 of 9	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720720

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

43468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25870

East Asian (EAS)

AF:

0.00

AC:

AN:

39474

South Asian (SAS)

AF:

0.00

AC:

AN:

83672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107316

Other (OTH)

AF:

0.00

AC:

AN:

60040

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Osteogenesis imperfecta with normal sclerae, dominant form

Pathogenic:1

Jun 05, 1988

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.6

H;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.9

D;.

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.95

Loss of methylation at R645 (P = 0.0599);.;

MVP

0.99

MPC

0.22

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over