rs149877855
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_000393.5(COL5A2):c.263C>A(p.Pro88His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 0 hom. )
Consequence
COL5A2
NM_000393.5 missense
NM_000393.5 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 9.90
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 -4 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.
BP6
Variant 2-189110284-G-T is Benign according to our data. Variant chr2-189110284-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213134.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 24 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.263C>A | p.Pro88His | missense_variant | 2/54 | ENST00000374866.9 | NP_000384.2 | |
COL5A2 | XM_011510573.4 | c.125C>A | p.Pro42His | missense_variant | 5/57 | XP_011508875.1 | ||
COL5A2 | XM_047443251.1 | c.125C>A | p.Pro42His | missense_variant | 7/59 | XP_047299207.1 | ||
COL5A2 | XM_047443252.1 | c.125C>A | p.Pro42His | missense_variant | 6/58 | XP_047299208.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.263C>A | p.Pro88His | missense_variant | 2/54 | 1 | NM_000393.5 | ENSP00000364000.3 | ||
COL5A2 | ENST00000649966.1 | c.125C>A | p.Pro42His | missense_variant | 2/11 | ENSP00000496785.1 | ||||
COL5A2 | ENST00000618828.1 | c.-368C>A | 5_prime_UTR_variant | 2/47 | 5 | ENSP00000482184.1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152088Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000135 AC: 34AN: 251272Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135804
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GnomAD4 exome AF: 0.000330 AC: 483AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 234AN XY: 727240
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GnomAD4 genome AF: 0.000158 AC: 24AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74286
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | COL5A2: PP3, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2024 | Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with cerebral palsy and a patient with hypermobility, lichen sclerosus, and ileostomy due to severe obstipation (PMID: 33161638, 30467950); This variant is associated with the following publications: (PMID: 30467950, 33161638, 22696272) - |
Ehlers-Danlos syndrome type 7A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2024 | Variant summary: COL5A2 c.263C>A (p.Pro88His) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251272 control chromosomes, predominantly at a frequency of 0.00027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 43.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A2 causing Ehlers-Danlos Syndrome phenotype (6.3e-06). To our knowledge, no occurrence of c.263C>A in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 213134). Based on the evidence outlined above, the variant was classified as likely benign. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2024 | 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. - |
Ehlers-Danlos syndrome, classic type, 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;.;.
Polyphen
D;D;.
Vest4
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