rs768171831

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000089.4(COL1A2):​c.2957C>T​(p.Pro986Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,002 control chromosomes in the GnomAD database, including 2 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 0.000053 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

4
6
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 1.76
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

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 Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, cardiac valvular type, ehlers-danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, high bone mass osteogenesis imperfecta, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, osteogenesis imperfecta type 4, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.13664246).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL1A2NM_000089.4 linkc.2957C>T p.Pro986Leu missense_variant Exon 45 of 52 ENST00000297268.11 NP_000080.2 P08123A0A0S2Z3H5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkc.2957C>T p.Pro986Leu missense_variant Exon 45 of 52 1 NM_000089.4 ENSP00000297268.6 P08123
COL1A2ENST00000478215.1 linkn.516C>T non_coding_transcript_exon_variant Exon 3 of 4 3
COL1A2ENST00000481570.5 linkn.2930C>T non_coding_transcript_exon_variant Exon 4 of 8 2
COL1A2ENST00000469732.1 linkn.*224C>T downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152140
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00125
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000123
AC:
31
AN:
251392
Hom.:
0
AF XY:
0.000191
AC XY:
26
AN XY:
135866
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 SAS exome
AF:
0.000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000636
AC:
93
AN:
1461862
Hom.:
1
Cov.:
31
AF XY:
0.0000949
AC XY:
69
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00101
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152140
Hom.:
1
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00125
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1
Apr 16, 2013
UCLA Clinical Genomics Center, UCLA
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Osteogenesis imperfecta Uncertain:1
Jun 25, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Jan 04, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has been reported as a maternally inherited variant in patients with clinical features of osteogenesis imperfecta (PMID: 25326637, 31061748); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25326637, 31061748) -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1
Sep 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Aug 01, 2024
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
0.075
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.19
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.97
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.14
T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
1.2
L;.
PrimateAI
Benign
0.28
T
PROVEAN
Pathogenic
-5.8
D;.
REVEL
Uncertain
0.32
Sift
Uncertain
0.016
D;.
Sift4G
Benign
0.063
T;T
Polyphen
0.030
B;.
Vest4
0.33
MutPred
0.36
Gain of catalytic residue at P986 (P = 0.0691);.;
MVP
0.64
MPC
0.22
ClinPred
0.65
D
GERP RS
4.4
Varity_R
0.15
gMVP
0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs768171831; hg19: chr7-94055323; API