rs201746779

Variant summary

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

The ENST00000297268.11(COL1A2):ā€‹c.3632T>Cā€‹(p.Ile1211Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,614,072 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 Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1211M) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 32)
Exomes š‘“: 0.000064 ( 0 hom. )

Consequence

COL1A2
ENST00000297268.11 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.13
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A2. . Gene score misZ 2.1491 (greater than the threshold 3.09). Trascript score misZ 3.5344 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.08632508).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A2NM_000089.4 linkuse as main transcriptc.3632T>C p.Ile1211Thr missense_variant 50/52 ENST00000297268.11 NP_000080.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkuse as main transcriptc.3632T>C p.Ile1211Thr missense_variant 50/521 NM_000089.4 ENSP00000297268 P1
COL1A2ENST00000464916.1 linkuse as main transcriptn.680T>C non_coding_transcript_exon_variant 2/42
COL1A2ENST00000481570.5 linkuse as main transcriptn.4413T>C non_coding_transcript_exon_variant 7/82

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152122
Hom.:
0
Cov.:
32
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
251160
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135730
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000636
AC:
93
AN:
1461832
Hom.:
0
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000728
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000659
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 28, 2021In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar (ClinVar Variant ID# 360970; Landrum et al., 2016) -
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Osteogenesis imperfecta Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Ehlers-danlos syndrome, arthrochalasia type, 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2024This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1211 of the COL1A2 protein (p.Ile1211Thr). This variant is present in population databases (rs201746779, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 360970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL1A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 03, 2023The p.I1211T variant (also known as c.3632T>C), located in coding exon 50 of the COL1A2 gene, results from a T to C substitution at nucleotide position 3632. The isoleucine at codon 1211 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.62
D;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.086
T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
1.9
L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.1
D;.
REVEL
Uncertain
0.40
Sift
Benign
0.069
T;.
Sift4G
Uncertain
0.022
D;D
Polyphen
0.0010
B;.
Vest4
0.39
MVP
0.76
MPC
0.27
ClinPred
0.15
T
GERP RS
4.1
Varity_R
0.13
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: rs201746779; hg19: chr7-94057710; COSMIC: COSV51956809; COSMIC: COSV51956809; API