rs139851311

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_000089.4(COL1A2):​c.3313G>A​(p.Gly1105Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,106 control chromosomes in the GnomAD database, including 5 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 0.00072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

7
5
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 8.14
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 Benign. Variant got -10 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=0.12622899).
BP6
Variant 7-94427672-G-A is Benign according to our data. Variant chr7-94427672-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360968.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=9}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00127 (1857/1461870) while in subpopulation SAS AF= 0.00288 (248/86258). AF 95% confidence interval is 0.00258. There are 5 homozygotes in gnomad4_exome. There are 950 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL1A2NM_000089.4 linkc.3313G>A p.Gly1105Ser missense_variant Exon 49 of 52 ENST00000297268.11 NP_000080.2 P08123A0A0S2Z3H5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkc.3313G>A p.Gly1105Ser missense_variant Exon 49 of 52 1 NM_000089.4 ENSP00000297268.6 P08123
COL1A2ENST00000464916.1 linkn.361G>A non_coding_transcript_exon_variant Exon 1 of 4 2
COL1A2ENST00000481570.5 linkn.4094G>A non_coding_transcript_exon_variant Exon 6 of 8 2

Frequencies

GnomAD3 genomes
AF:
0.000717
AC:
109
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000411
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000676
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000995
AC:
250
AN:
251270
Hom.:
0
AF XY:
0.00101
AC XY:
137
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.00176
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
Gnomad SAS exome
AF:
0.00238
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.000784
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.00127
AC:
1857
AN:
1461870
Hom.:
5
Cov.:
33
AF XY:
0.00131
AC XY:
950
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00190
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000705
Gnomad4 SAS exome
AF:
0.00288
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.00125
Gnomad4 OTH exome
AF:
0.00139
GnomAD4 genome
AF:
0.000716
AC:
109
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.000739
AC XY:
55
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.000409
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000676
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000890
Hom.:
1
Bravo
AF:
0.000899
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00174
AC:
15
ExAC
AF:
0.000972
AC:
118
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.000872
EpiControl
AF:
0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Sep 06, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The COL1A2 c.3313G>A; p.Gly1105Ser variant (rs139851311; ClinVar Variation ID: 360968) is reported in the literature in several individuals affected with osteogenesis imperfecta or Ehlers-Danlos Syndrome, though it was not demonstrated to cause disease (Junkiert-Czarnecka 2022, Lin 2024, Mei 2022, Stephen 2014, Zhang 2012). This variant is found in the South Asian population with an overall allele frequency of 0.24% (73/30610 alleles) in the Genome Aggregation Database (v2.1.1). The glycine at codon 1105 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.783). It is unclear if this glycine residue is incorporated into the collagen triple helix domain. While the population frequency of this variant is inconsistent with disease, given the lack of clinical and functional data, the significance of the p.Gly1105Ser variant is uncertain at this time. References: Junkiert-Czarnecka A et al. Next-Generation Sequencing of Connective Tissue Genes in Patients with Classical Ehlers-Danlos Syndrome. Curr Issues Mol Biol. 2022 Mar 25;44(4):1472-1478. PMID: 35723357. Lin X et al. Genotype-phenotype relationship and comparison between eastern and western patients with osteogenesis imperfecta. J Endocrinol Invest. 2024 Jan;47(1):67-77. PMID: 37270749. Mei Y et al. Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. PMID: 35909573. Stephen J et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. Am J Med Genet A. 2014 Jun;164A(6):1482-9. PMID: 24668929. Zhang ZL et al. The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. J Bone Miner Metab. 2012 Jan;30(1):69-77. PMID: 21667357. -

Mar 06, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL1A2: BS1 -

not specified Benign:2
Oct 23, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 25, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: COL1A2 c.3313G>A (p.Gly1105Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 251270 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 85.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Osteogenesis Imperfecta phenotype (2.8e-05). c.3313G>A has been reported in the literature in heterozygous individuals affected with Osteogenesis Imperfecta (Mrosk_2018, Zhang_2012). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (COL1A1 c.2299G>A , p.Gly767Ser), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 360968). Based on the evidence outlined above, the variant was classified as likely benign. -

Osteogenesis imperfecta Benign:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dec 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Uncertain:1
Feb 10, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Connective tissue disorder Uncertain:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-danlos syndrome, arthrochalasia type, 2 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Mar 05, 2020
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
0.089
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.50
CADD
Uncertain
23
DANN
Benign
0.90
DEOGEN2
Uncertain
0.66
D;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.73
T;T
M_CAP
Pathogenic
0.39
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
M;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.4
D;.
REVEL
Pathogenic
0.78
Sift
Benign
0.18
T;.
Sift4G
Benign
0.17
T;T
Polyphen
1.0
D;.
Vest4
0.87
MVP
0.95
MPC
0.21
ClinPred
0.048
T
GERP RS
5.8
Varity_R
0.72
gMVP
0.91

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: rs139851311; hg19: chr7-94056984; API