rs151061939

Positions:

• chr3-53179675-G-A
• chr3-53179675-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006254.4(PRKCD):​c.214G>A​(p.Val72Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

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]

PRKCD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22277823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCD	NM_006254.4	c.214G>A	p.Val72Met	missense_variant	4/19	ENST00000330452.8	NP_006245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCD	ENST00000330452.8	c.214G>A	p.Val72Met	missense_variant	4/19	1	NM_006254.4	ENSP00000331602.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248596 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134488

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460762 Hom.: 0 Cov.: 45 AF XY: 0.00000275 AC XY: 2 AN XY: 726546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 837398). This variant has not been reported in the literature in individuals affected with PRKCD-related conditions. This variant is present in population databases (rs151061939, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 72 of the PRKCD protein (p.Val72Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T;T;T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;.;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.6	.;L;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Uncertain	0.0070	D;T;T;D;D
Polyphen		0.21, 0.99	.;B;B;.;D
Vest4		0.57, 0.57
MutPred		0.40		Gain of catalytic residue at V68 (P = 0.0243);Gain of catalytic residue at V68 (P = 0.0243);Gain of catalytic residue at V68 (P = 0.0243);Gain of catalytic residue at V68 (P = 0.0243);Gain of catalytic residue at V68 (P = 0.0243);
MVP		0.78
MPC		1.5
ClinPred		0.28	T
GERP RS		5.0
Varity_R		0.26
gMVP		0.71

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

Other links and lift over

dbSNP: rs151061939; hg19: chr3-53213691;