NM_001197026.2:c.221A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001197026.2(PLEKHA8):​c.221A>G​(p.Lys74Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PLEKHA8
NM_001197026.2 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.38

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.28305256).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLEKHA8NM_001197026.2 linkc.221A>G p.Lys74Arg missense_variant Exon 3 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.221A>G p.Lys74Arg missense_variant Exon 3 of 14 1 NM_001197026.2 ENSP00000397947.1 Q96JA3-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251076
AF XY:
0.0000442
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000705
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000121
AC:
177
AN:
1461610
Hom.:
0
Cov.:
30
AF XY:
0.000120
AC XY:
87
AN XY:
727124
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33458
American (AMR)
AF:
0.00
AC:
0
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26110
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86224
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000152
AC:
169
AN:
1111858
Other (OTH)
AF:
0.000116
AC:
7
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.472
Heterozygous variant carriers
0
10
20
29
39
49
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.0000460
AC:
7
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74376
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41454
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.446
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

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:
0.0000282
Hom.:
0
Bravo
AF:
0.0000378
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 17, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.221A>G (p.K74R) alteration is located in exon 3 (coding exon 3) of the PLEKHA8 gene. This alteration results from a A to G substitution at nucleotide position 221, causing the lysine (K) at amino acid position 74 to be replaced by an arginine (R). 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
0.13
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;.;.;T;T
Eigen
Benign
-0.068
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;.
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.28
T;T;T;T;T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Benign
0.33
N;.;N;N;.;.
PhyloP100
5.4
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.39
N;.;N;N;N;N
REVEL
Benign
0.27
Sift
Benign
0.52
T;.;T;T;T;T
Sift4G
Benign
0.80
T;T;T;T;T;T
Polyphen
0.026, 1.0
.;.;B;D;.;.
Vest4
0.24
MVP
0.85
MPC
0.32
ClinPred
0.17
T
GERP RS
5.4
Varity_R
0.066
gMVP
0.39
Mutation Taster
=92/8
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: rs758687922; hg19: chr7-30085889; API