1-36097826-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005202.4(COL8A2):​c.1855G>A​(p.Val619Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

COL8A2
NM_005202.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Publications

2 publications found
Variant links:
Genes affected
COL8A2 (HGNC:2216): (collagen type VIII alpha 2 chain) This gene encodes the alpha 2 chain of type VIII collagen. This protein is a major component of the basement membrane of the corneal endothelium and forms homo- or heterotrimers with alpha 1 (VIII) type collagens. Defects in this gene are associated with Fuchs endothelial corneal dystrophy and posterior polymorphous corneal dystrophy type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]
COL8A2 Gene-Disease associations (from GenCC):
  • corneal dystrophy, Fuchs endothelial, 1
    Inheritance: AD Classification: STRONG Submitted by: G2P
  • posterior polymorphous corneal dystrophy 2
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Fuchs' endothelial dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • posterior polymorphous corneal dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0758453).
BS2
High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL8A2NM_005202.4 linkc.1855G>A p.Val619Ile missense_variant Exon 4 of 4 ENST00000397799.2 NP_005193.1 P25067
COL8A2NM_001294347.2 linkc.1660G>A p.Val554Ile missense_variant Exon 4 of 4 NP_001281276.1 P25067E9PP49

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL8A2ENST00000397799.2 linkc.1855G>A p.Val619Ile missense_variant Exon 4 of 4 5 NM_005202.4 ENSP00000380901.1 P25067
COL8A2ENST00000481785.1 linkc.1660G>A p.Val554Ile missense_variant Exon 2 of 2 1 ENSP00000436433.1 E9PP49
COL8A2ENST00000303143.9 linkc.1855G>A p.Val619Ile missense_variant Exon 2 of 2 2 ENSP00000305913.4 P25067

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152246
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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
GnomAD2 exomes
AF:
0.0000717
AC:
18
AN:
250988
AF XY:
0.0000589
show subpopulations
Gnomad AFR exome
AF:
0.000678
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461128
Hom.:
0
Cov.:
37
AF XY:
0.0000248
AC XY:
18
AN XY:
726894
show subpopulations
African (AFR)
AF:
0.000478
AC:
16
AN:
33480
American (AMR)
AF:
0.0000894
AC:
4
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.000126
AC:
5
AN:
39700
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52672
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000629
AC:
7
AN:
1112002
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152246
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.000482
AC:
20
AN:
41470
American (AMR)
AF:
0.000262
AC:
4
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.531
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.000257
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Mar 14, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1855G>A (p.V619I) alteration is located in exon 2 (coding exon 2) of the COL8A2 gene. This alteration results from a G to A substitution at nucleotide position 1855, causing the valine (V) at amino acid position 619 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Benign
0.14
T;T;.
Eigen
Benign
-0.14
Eigen_PC
Benign
0.029
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.82
.;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.076
T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
0.52
N;N;.
PhyloP100
2.3
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
0.020
N;N;N
REVEL
Benign
0.16
Sift
Benign
0.62
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.38
B;B;.
Vest4
0.12
MVP
0.39
MPC
0.38
ClinPred
0.027
T
GERP RS
4.6
Varity_R
0.080
gMVP
0.17
Mutation Taster
=90/10
polymorphism

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

Other links and lift over

dbSNP: rs150169820; hg19: chr1-36563427; COSMIC: COSV57442015; COSMIC: COSV57442015; API