rs1553514920
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_000393.5(COL5A2):c.2168G>A(p.Gly723Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
COL5A2
NM_000393.5 missense
NM_000393.5 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 6.15
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_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.2168G>A | p.Gly723Glu | missense_variant | 33/54 | ENST00000374866.9 | NP_000384.2 | |
COL5A2 | XM_011510573.4 | c.2030G>A | p.Gly677Glu | missense_variant | 36/57 | XP_011508875.1 | ||
COL5A2 | XM_047443251.1 | c.2030G>A | p.Gly677Glu | missense_variant | 38/59 | XP_047299207.1 | ||
COL5A2 | XM_047443252.1 | c.2030G>A | p.Gly677Glu | missense_variant | 37/58 | XP_047299208.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.2168G>A | p.Gly723Glu | missense_variant | 33/54 | 1 | NM_000393.5 | ENSP00000364000 | P1 | |
COL5A2 | ENST00000618828.1 | c.1007G>A | p.Gly336Glu | missense_variant | 26/47 | 5 | ENSP00000482184 | |||
COL5A2 | ENST00000470524.2 | n.274G>A | non_coding_transcript_exon_variant | 6/8 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727198
GnomAD4 exome
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1
AN:
1461776
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32
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1
AN XY:
727198
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 14, 2017 | In summary, this variant is a novel missense change that affects a residue critical for protein structure, stability and function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and missense variants at these glycine residues in COL5A2 are more frequently observed in individuals with disease than in the general population (PMID: 22696272, 23587214). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A2-related disease. This sequence change replaces glycine with glutamic acid at codon 723 of the COL5A2 protein (p.Gly723Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;T;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;.;D
Vest4
MutPred
Gain of solvent accessibility (P = 0.0062);.;Gain of solvent accessibility (P = 0.0062);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at