rs1792222189

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001197026.2(PLEKHA8):​c.557C>A​(p.Pro186Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P186L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PLEKHA8
NM_001197026.2 missense

Scores

5
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.82

Publications

0 publications found
Variant links:
Genes affected
PLEKHA8 (HGNC:30037): (pleckstrin homology domain containing A8) Enables several functions, including ceramide binding activity; glycolipid transfer activity; and phosphatidylinositol-4-phosphate binding activity. Involved in ER to Golgi ceramide transport. Located in nucleoplasm and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLEKHA8NM_001197026.2 linkc.557C>A p.Pro186Gln missense_variant Exon 5 of 14 ENST00000449726.6 NP_001183955.1 Q96JA3-1A0A2P1JJM6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLEKHA8ENST00000449726.6 linkc.557C>A p.Pro186Gln missense_variant Exon 5 of 14 1 NM_001197026.2 ENSP00000397947.1 Q96JA3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461820
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727216
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111972
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.467
Heterozygous variant carriers
0
1
1
2
2
3
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
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.028
T;.;.;.;T;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;.
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.64
D;D;D;D;D;D
MetaSVM
Uncertain
-0.27
T
PhyloP100
7.8
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.3
D;.;D;D;D;D
REVEL
Benign
0.27
Sift
Uncertain
0.0020
D;.;D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D;D;D
Polyphen
1.0
D;.;D;D;.;.
Vest4
0.62
MutPred
0.41
Loss of glycosylation at P186 (P = 0.0127);Loss of glycosylation at P186 (P = 0.0127);Loss of glycosylation at P186 (P = 0.0127);Loss of glycosylation at P186 (P = 0.0127);Loss of glycosylation at P186 (P = 0.0127);.;
MVP
0.68
MPC
0.96
ClinPred
0.98
D
GERP RS
6.1
Varity_R
0.32
gMVP
0.57
Mutation Taster
=31/69
disease causing

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: rs1792222189; hg19: chr7-30088958; API