1-204230429-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014935.5(PLEKHA6):​c.2567G>A​(p.Arg856Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,581,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PLEKHA6
NM_014935.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16991618).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLEKHA6NM_014935.5 linkuse as main transcriptc.2567G>A p.Arg856Gln missense_variant 18/23 ENST00000272203.8 NP_055750.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLEKHA6ENST00000272203.8 linkuse as main transcriptc.2567G>A p.Arg856Gln missense_variant 18/231 NM_014935.5 ENSP00000272203 P2
PLEKHA6ENST00000637508.1 linkuse as main transcriptc.2939G>A p.Arg980Gln missense_variant 22/275 ENSP00000490182 A2
PLEKHA6ENST00000414478.1 linkuse as main transcriptc.2627G>A p.Arg876Gln missense_variant 18/235 ENSP00000402046

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000509
AC:
1
AN:
196550
Hom.:
0
AF XY:
0.00000947
AC XY:
1
AN XY:
105616
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000117
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000280
AC:
4
AN:
1429616
Hom.:
0
Cov.:
31
AF XY:
0.00000424
AC XY:
3
AN XY:
707858
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:
0.0000123
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000182
Gnomad4 OTH exome
AF:
0.0000169
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.00000831
AC:
1
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

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 GeneticsJul 06, 2021The c.2567G>A (p.R856Q) alteration is located in exon 18 (coding exon 16) of the PLEKHA6 gene. This alteration results from a G to A substitution at nucleotide position 2567, causing the arginine (R) at amino acid position 856 to be replaced by a glutamine (Q). 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
0.092
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.024
T;T;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;.;.
MutationTaster
Benign
0.81
N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.82
N;.;N
REVEL
Benign
0.055
Sift
Benign
0.32
T;.;T
Sift4G
Benign
0.46
T;.;T
Polyphen
1.0
D;.;.
Vest4
0.093
MutPred
0.29
Loss of MoRF binding (P = 0.0247);.;.;
MVP
0.20
MPC
0.20
ClinPred
0.64
D
GERP RS
5.2
Varity_R
0.11
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs774866824; hg19: chr1-204199557; COSMIC: COSV55331752; API