rs758412337
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_000393.5(COL5A2):c.3488A>G(p.Gln1163Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,454,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
COL5A2
NM_000393.5 missense
NM_000393.5 missense
Scores
12
6
Clinical Significance
Conservation
PhyloP100: 3.31
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 where missense usually causes diseases, COL5A2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.30958545).
BS2
?
High AC in GnomAdExome at 16 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.3488A>G | p.Gln1163Arg | missense_variant | 49/54 | ENST00000374866.9 | |
COL5A2 | XM_011510573.4 | c.3350A>G | p.Gln1117Arg | missense_variant | 52/57 | ||
COL5A2 | XM_047443251.1 | c.3350A>G | p.Gln1117Arg | missense_variant | 54/59 | ||
COL5A2 | XM_047443252.1 | c.3350A>G | p.Gln1117Arg | missense_variant | 53/58 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.3488A>G | p.Gln1163Arg | missense_variant | 49/54 | 1 | NM_000393.5 | P1 | |
COL5A2 | ENST00000618828.1 | c.2327A>G | p.Gln776Arg | missense_variant | 42/47 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000666 AC: 16AN: 240154Hom.: 0 AF XY: 0.0000540 AC XY: 7AN XY: 129550
GnomAD3 exomes
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GnomAD4 exome AF: 0.0000131 AC: 19AN: 1454516Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 722906
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2017 | The p.Q1163R variant (also known as c.3488A>G), located in coding exon 49 of the COL5A2 gene, results from an A to G substitution at nucleotide position 3488. The glutamine at codon 1163 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ehlers-Danlos syndrome, classic type, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 15, 2022 | This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 0.04% [13/33820]; https://gnomad.broadinstitute.org/variant/2-189907483-T-C?dataset=gnomad_r2_1), and in ClinVar (Variation ID: 408279). Evolutionary conservation and computational prediction tools are unclear for this variant. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Benign
T;T;.
Polyphen
D;.;D
Vest4
MutPred
Gain of methylation at Q1163 (P = 0.0067);.;Gain of methylation at Q1163 (P = 0.0067);
MVP
MPC
ClinPred
T
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