1-204229025-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014935.5(PLEKHA6):ā€‹c.2663A>Gā€‹(p.His888Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

PLEKHA6
NM_014935.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20
Variant links:
Genes affected
PLEKHA6 (HGNC:17053): (pleckstrin homology domain containing A6)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06629738).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLEKHA6NM_014935.5 linkuse as main transcriptc.2663A>G p.His888Arg missense_variant 19/23 ENST00000272203.8 NP_055750.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLEKHA6ENST00000272203.8 linkuse as main transcriptc.2663A>G p.His888Arg missense_variant 19/231 NM_014935.5 ENSP00000272203 P2
PLEKHA6ENST00000637508.1 linkuse as main transcriptc.3035A>G p.His1012Arg missense_variant 23/275 ENSP00000490182 A2
PLEKHA6ENST00000414478.1 linkuse as main transcriptc.2723A>G p.His908Arg missense_variant 19/235 ENSP00000402046

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251450
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 26, 2024The c.2663A>G (p.H888R) alteration is located in exon 19 (coding exon 17) of the PLEKHA6 gene. This alteration results from a A to G substitution at nucleotide position 2663, causing the histidine (H) at amino acid position 888 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
0.054
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
16
DANN
Benign
0.75
DEOGEN2
Benign
0.018
T;T;.
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.59
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.25
T;T;T
M_CAP
Benign
0.0046
T
MetaRNN
Benign
0.066
T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.0
N;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.020
N;.;N
REVEL
Benign
0.037
Sift
Benign
0.29
T;.;T
Sift4G
Benign
1.0
T;.;T
Polyphen
0.0
B;.;.
Vest4
0.20
MutPred
0.17
Gain of solvent accessibility (P = 0.0837);.;.;
MVP
0.043
MPC
0.13
ClinPred
0.046
T
GERP RS
3.1
Varity_R
0.049
gMVP
0.13

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: rs773428693; hg19: chr1-204198153; API