rs149877855

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

Scores

1
11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 9.90
Variant links:
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]

Genome browser will be placed here

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
COL5A2NM_000393.5 linkuse as main transcriptc.263C>A p.Pro88His missense_variant 2/54 ENST00000374866.9 NP_000384.2 P05997
COL5A2XM_011510573.4 linkuse as main transcriptc.125C>A p.Pro42His missense_variant 5/57 XP_011508875.1
COL5A2XM_047443251.1 linkuse as main transcriptc.125C>A p.Pro42His missense_variant 7/59 XP_047299207.1
COL5A2XM_047443252.1 linkuse as main transcriptc.125C>A p.Pro42His missense_variant 6/58 XP_047299208.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL5A2ENST00000374866.9 linkuse as main transcriptc.263C>A p.Pro88His missense_variant 2/541 NM_000393.5 ENSP00000364000.3 P05997
COL5A2ENST00000649966.1 linkuse as main transcriptc.125C>A p.Pro42His missense_variant 2/11 ENSP00000496785.1 A0A3B3IRH9
COL5A2ENST00000618828.1 linkuse as main transcriptc.-368C>A 5_prime_UTR_variant 2/475 ENSP00000482184.1 A0A087WYX9

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000323
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251272
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135804
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000273
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000330
AC:
483
AN:
1461874
Hom.:
0
Cov.:
33
AF XY:
0.000322
AC XY:
234
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.000424
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152088
Hom.:
0
Cov.:
32
AF XY:
0.000162
AC XY:
12
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000323
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000224
Hom.:
0
Bravo
AF:
0.000155
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000382
EpiControl
AF:
0.000237

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 submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023COL5A2: PP3, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 03, 2024Not 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 submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 23, 2024Variant 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 submitterclinical testingAmbry GeneticsJun 12, 2024This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.071
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;T;.
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.74
.;T;T
M_CAP
Benign
0.072
D
MetaRNN
Uncertain
0.72
D;D;D
MetaSVM
Uncertain
0.019
D
MutationAssessor
Uncertain
2.8
M;M;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-4.2
D;.;.
REVEL
Uncertain
0.56
Sift
Uncertain
0.0010
D;.;.
Sift4G
Uncertain
0.0030
D;.;.
Polyphen
1.0
D;D;.
Vest4
0.66
MVP
0.60
MPC
1.0
ClinPred
0.77
D
GERP RS
5.4
Varity_R
0.33
gMVP
0.68

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: rs149877855; hg19: chr2-189975010; API