rs369236318
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_006254.4(PRKCD):āc.715A>Gā(p.Met239Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.0000055 ( 0 hom. )
Consequence
PRKCD
NM_006254.4 missense
NM_006254.4 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 7.28
Genes affected
PRKCD (HGNC:9399): (protein kinase C delta) The protein encoded by this gene is a member of the protein kinase C family of serine- and threonine-specific protein kinases. The encoded protein is activated by diacylglycerol and is both a tumor suppressor and a positive regulator of cell cycle progression. Also, this protein can positively or negatively regulate apoptosis. Defects in this gene are a cause of autoimmune lymphoproliferative syndrome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRKCD. . Gene score misZ 3.1145 (greater than the threshold 3.09). Trascript score misZ 3.8606 (greater than threshold 3.09). GenCC has associacion of gene with common variable immunodeficiency, autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD, autoimmune lymphoproliferative syndrome, autosomal systemic lupus erythematosus type 16.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKCD | NM_006254.4 | c.715A>G | p.Met239Val | missense_variant | 9/19 | ENST00000330452.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKCD | ENST00000330452.8 | c.715A>G | p.Met239Val | missense_variant | 9/19 | 1 | NM_006254.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727248
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2019 | This variant is present in population databases (rs369236318, ExAC 0.02%). This sequence change replaces methionine with valine at codon 239 of the PRKCD protein (p.Met239Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant has not been reported in the literature in individuals with a PRKCD-related disease. In summary, this variant has uncertain impact on PRKCD function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at