rs779153546
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBP6BS2
The NM_000393.5(COL5A2):c.376G>A(p.Gly126Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,612,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 1 hom. )
Consequence
COL5A2
NM_000393.5 missense
NM_000393.5 missense
Scores
8
5
5
Clinical Significance
Conservation
PhyloP100: 4.77
Genes affected
COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, COL5A2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.857
BP6
?
Variant 2-189098753-C-T is Benign according to our data. Variant chr2-189098753-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213140.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
BS2
?
High AC in GnomAd at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.376G>A | p.Gly126Ser | missense_variant | 5/54 | ENST00000374866.9 | |
COL5A2 | XM_011510573.4 | c.238G>A | p.Gly80Ser | missense_variant | 8/57 | ||
COL5A2 | XM_047443251.1 | c.238G>A | p.Gly80Ser | missense_variant | 10/59 | ||
COL5A2 | XM_047443252.1 | c.238G>A | p.Gly80Ser | missense_variant | 9/58 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.376G>A | p.Gly126Ser | missense_variant | 5/54 | 1 | NM_000393.5 | P1 | |
COL5A2 | ENST00000649966.1 | c.238G>A | p.Gly80Ser | missense_variant | 5/11 | ||||
COL5A2 | ENST00000618828.1 | c.-255G>A | 5_prime_UTR_variant | 5/47 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251232Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135798
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1460642Hom.: 1 Cov.: 29 AF XY: 0.0000151 AC XY: 11AN XY: 726664
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2020 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; Stenson et al., 2014); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 213140; Landrum et al., 2016) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 26, 2021 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2022 | The p.G126S variant (also known as c.376G>A), located in coding exon 5 of the COL5A2 gene, results from a G to A substitution at nucleotide position 376. The glycine at codon 126 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort; however, clinical details were limited and an additional alteration in another cardiac-related gene was identified (Salfati EL et al. Genome Med, 2019 12;11:83). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
COL5A2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 08, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.
REVEL
Pathogenic
Sift
Benign
T;.;.
Sift4G
Benign
T;.;.
Polyphen
D;D;.
Vest4
MutPred
Gain of glycosylation at G126 (P = 0.0135);Gain of glycosylation at G126 (P = 0.0135);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at