rs62184175

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The ENST00000374866.9(COL5A2):​c.3689C>T​(p.Thr1230Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. T1230R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

COL5A2
ENST00000374866.9 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66
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 -5 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.17468837).
BS2
High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL5A2NM_000393.5 linkuse as main transcriptc.3689C>T p.Thr1230Ile missense_variant 51/54 ENST00000374866.9 NP_000384.2
COL5A2XM_011510573.4 linkuse as main transcriptc.3551C>T p.Thr1184Ile missense_variant 54/57 XP_011508875.1
COL5A2XM_047443251.1 linkuse as main transcriptc.3551C>T p.Thr1184Ile missense_variant 56/59 XP_047299207.1
COL5A2XM_047443252.1 linkuse as main transcriptc.3551C>T p.Thr1184Ile missense_variant 55/58 XP_047299208.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL5A2ENST00000374866.9 linkuse as main transcriptc.3689C>T p.Thr1230Ile missense_variant 51/541 NM_000393.5 ENSP00000364000 P1
COL5A2ENST00000618828.1 linkuse as main transcriptc.2528C>T p.Thr843Ile missense_variant 44/475 ENSP00000482184

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250610
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135574
show subpopulations
Gnomad AFR exome
AF:
0.0000625
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:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461766
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 21, 2024The p.T1230I variant (also known as c.3689C>T), located in coding exon 51 of the COL5A2 gene, results from a C to T substitution at nucleotide position 3689. The threonine at codon 1230 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.26
T;T;T
Eigen
Benign
-0.13
Eigen_PC
Benign
0.086
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.76
.;T;T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Benign
1.2
L;.;L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.80
N;.;.
REVEL
Benign
0.26
Sift
Benign
0.42
T;.;.
Sift4G
Benign
0.45
T;T;.
Polyphen
0.021
B;.;B
Vest4
0.28
MutPred
0.47
Loss of phosphorylation at T1230 (P = 0.0143);.;Loss of phosphorylation at T1230 (P = 0.0143);
MVP
0.33
MPC
0.28
ClinPred
0.16
T
GERP RS
5.3
Varity_R
0.093
gMVP
0.52

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: rs62184175; hg19: chr2-189904234; API