rs2306574

chr3-53188745-C-Achr3-53188745-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_006254.4(PRKCD):c.1441C>A(p.Leu481Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L481L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKCD
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCD	NM_006254.4	c.1441C>A	p.Leu481Met	missense_variant	16/19	ENST00000330452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCD	ENST00000330452.8	c.1441C>A	p.Leu481Met	missense_variant	16/19	1	NM_006254.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	8.7e-11	P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.83		Gain of catalytic residue at L481 (P = 0.1187);Gain of catalytic residue at L481 (P = 0.1187);
MVP		0.87
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.86
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: rs2306574; hg19: chr3-53222761;