2-218622858-G-A

Variant summary

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

The NM_032726.4(PLCD4):​c.752G>A​(p.Arg251His) variant causes a missense change. The variant allele was found at a frequency of 0.0000868 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

PLCD4
NM_032726.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70
Variant links:
Genes affected
PLCD4 (HGNC:9062): (phospholipase C delta 4) This gene encodes a member of the delta class of phospholipase C enzymes. Phospholipase C enzymes play a critical role in many cellular processes by hydrolyzing phosphatidylinositol 4,5-bisphosphate into two intracellular second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. Expression of this gene may be a marker for cancer. [provided by RefSeq, Jan 2011]

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=0.026826143).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLCD4NM_032726.4 linkuse as main transcriptc.752G>A p.Arg251His missense_variant 6/16 ENST00000450993.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLCD4ENST00000450993.7 linkuse as main transcriptc.752G>A p.Arg251His missense_variant 6/161 NM_032726.4 P1Q9BRC7-1

Frequencies

GnomAD3 genomes
AF:
0.000269
AC:
41
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000892
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000120
AC:
30
AN:
248984
Hom.:
0
AF XY:
0.0000962
AC XY:
13
AN XY:
135092
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000677
AC:
99
AN:
1461398
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
726984
show subpopulations
Gnomad4 AFR exome
AF:
0.00123
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000269
AC:
41
AN:
152332
Hom.:
0
Cov.:
33
AF XY:
0.000201
AC XY:
15
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000890
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.000344
ESP6500AA
AF:
0.00126
AC:
5
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000157
AC:
19

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 GeneticsMay 15, 2024The c.752G>A (p.R251H) alteration is located in exon 6 (coding exon 5) of the PLCD4 gene. This alteration results from a G to A substitution at nucleotide position 752, causing the arginine (R) at amino acid position 251 to be replaced by a histidine (H). 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
0.073
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D;D;T
Eigen
Benign
0.15
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.69
T;.;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.027
T;T;T
MetaSVM
Benign
-0.56
T
MutationAssessor
Uncertain
2.8
M;M;.
MutationTaster
Benign
0.69
N;N;N
PrimateAI
Benign
0.22
T
PROVEAN
Uncertain
-3.4
D;D;D
REVEL
Benign
0.16
Sift
Benign
0.056
T;T;D
Sift4G
Uncertain
0.026
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.17
MVP
0.68
MPC
0.77
ClinPred
0.12
T
GERP RS
3.9
Varity_R
0.20
gMVP
0.28

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: rs184719765; hg19: chr2-219487581; API