rs759604513
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_000393.5(COL5A2):c.284T>A(p.Val95Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V95L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
COL5A2
NM_000393.5 missense
NM_000393.5 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 3.84
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 -3 ACMG points.
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.
BS2
High AC in GnomAdExome4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.284T>A | p.Val95Asp | missense_variant | 2/54 | ENST00000374866.9 | |
COL5A2 | XM_011510573.4 | c.146T>A | p.Val49Asp | missense_variant | 5/57 | ||
COL5A2 | XM_047443251.1 | c.146T>A | p.Val49Asp | missense_variant | 7/59 | ||
COL5A2 | XM_047443252.1 | c.146T>A | p.Val49Asp | missense_variant | 6/58 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.284T>A | p.Val95Asp | missense_variant | 2/54 | 1 | NM_000393.5 | P1 | |
COL5A2 | ENST00000649966.1 | c.146T>A | p.Val49Asp | missense_variant | 2/11 | ||||
COL5A2 | ENST00000618828.1 | c.-347T>A | 5_prime_UTR_variant | 2/47 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251354Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135846
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461836Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727222
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74340
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In 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 (Symoens et al., 2012; HGMD) - |
Ehlers-Danlos syndrome, classic type, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces valine with aspartic acid at codon 95 of the COL5A2 protein (p.Val95Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is present in population databases (rs759604513, ExAC 0.007%). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213135). 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. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
.;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;.;.
Polyphen
B;B;.
Vest4
MutPred
Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP
MPC
ClinPred
D
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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