3-53178510-G-A

Variant names:

• chr3-53178510-G-A
• rs1703300399
• NM_006254.4:c.88G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006254.4(PRKCD):​c.88G>A​(p.Val30Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V30V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal systemic lupus erythematosus type 16

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCD	NM_006254.4	c.88G>A	p.Val30Met	missense_variant	Exon 3 of 19	ENST00000330452.8	NP_006245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCD	ENST00000330452.8	c.88G>A	p.Val30Met	missense_variant	Exon 3 of 19	1	NM_006254.4	ENSP00000331602.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460780 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726676

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111760

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

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

Jul 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 970582). This variant has not been reported in the literature in individuals affected with PRKCD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 30 of the PRKCD protein (p.Val30Met). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.8	.;L;L;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D;N;N;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;T;T;D;D
Polyphen		1.0, 1.0	.;D;D;.;D
Vest4		0.47, 0.47
MutPred		0.67		Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);
MVP		0.85
MPC		1.5
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.54
gMVP		0.68
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs1703300399; hg19: chr3-53212526;