rs2230494

Positions:

• chr3-53186199-G-A
• chr3-53186199-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006254.4(PRKCD):​c.1119G>A​(p.Glu373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,613,704 control chromosomes in the GnomAD database, including 60,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6478 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53992 hom.)
• Consequence: PRKCD NM_006254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.23

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-53186199-G-A is Benign according to our data. Variant chr3-53186199-G-A is described in ClinVar as [Benign]. Clinvar id is 403345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCD	NM_006254.4	c.1119G>A	p.Glu373=	synonymous_variant	13/19	ENST00000330452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCD	ENST00000330452.8	c.1119G>A	p.Glu373=	synonymous_variant	13/19	1	NM_006254.4	P1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43862 AN: 151990 Hom.: 6470 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.271 AC: 67887 AN: 250708 Hom.: 9203 AF XY: 0.271 AC XY: 36747 AN XY: 135488

Gnomad AFR exome AF: 0.328

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.257

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.270 AC: 394688 AN: 1461596 Hom.: 53992 Cov.: 39 AF XY: 0.271 AC XY: 196889 AN XY: 727092

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.273

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.289 AC: 43906 AN: 152108 Hom.: 6478 Cov.: 32 AF XY: 0.287 AC XY: 21371 AN XY: 74344

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.209

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.296

Alfa AF: 0.277 Hom.: 3812

Bravo AF: 0.290

Asia WGS AF: 0.229 AC: 796 AN: 3478

EpiCase AF: 0.288

EpiControl AF: 0.290

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 47% of patients studied by a panel of primary immunodeficiencies. Number of patients: 45. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.4
DANN	Benign	0.54

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: rs2230494; hg19: chr3-53220215; COSMIC: COSV57846818; COSMIC: COSV57846818;