rs2230493

Variant names:

• chr3-53179641-T-C
• rs2230493
• NM_006254.4:c.180T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006254.4(PRKCD):​c.180T>C​(p.Asp60Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,930 control chromosomes in the GnomAD database, including 21,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1364 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20035 hom.)
• Consequence: PRKCD NM_006254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.426
• Publications: 20 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-53179641-T-C is Benign according to our data. Variant chr3-53179641-T-C is described in ClinVar as [Benign]. Clinvar id is 403344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCD	NM_006254.4	c.180T>C	p.Asp60Asp	synonymous_variant	Exon 4 of 19	ENST00000330452.8	NP_006245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCD	ENST00000330452.8	c.180T>C	p.Asp60Asp	synonymous_variant	Exon 4 of 19	1	NM_006254.4	ENSP00000331602.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18706 AN: 152136 Hom.: 1363 Cov.: 33

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.127 AC: 31911 AN: 250908 AF XY: 0.133

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.0687

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0179

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.160 AC: 233451 AN: 1461676 Hom.: 20035 Cov.: 55 AF XY: 0.160 AC XY: 116659 AN XY: 727116

African (AFR) AF: 0.0603 AC: 2019 AN: 33478

American (AMR) AF: 0.0720 AC: 3218 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 3871 AN: 26134

East Asian (EAS) AF: 0.0134 AC: 533 AN: 39700

South Asian (SAS) AF: 0.161 AC: 13892 AN: 86226

European-Finnish (FIN) AF: 0.124 AC: 6597 AN: 53410

Middle Eastern (MID) AF: 0.164 AC: 948 AN: 5764

European-Non Finnish (NFE) AF: 0.174 AC: 193503 AN: 1111868

Other (OTH) AF: 0.147 AC: 8870 AN: 60388

GnomAD4 genome AF: 0.123 AC: 18703 AN: 152254 Hom.: 1364 Cov.: 33 AF XY: 0.121 AC XY: 8985 AN XY: 74460

African (AFR) AF: 0.0631 AC: 2623 AN: 41546

American (AMR) AF: 0.101 AC: 1552 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 512 AN: 3470

East Asian (EAS) AF: 0.0173 AC: 90 AN: 5190

South Asian (SAS) AF: 0.153 AC: 736 AN: 4822

European-Finnish (FIN) AF: 0.121 AC: 1290 AN: 10620

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11440 AN: 67990

Other (OTH) AF: 0.123 AC: 259 AN: 2108

Alfa AF: 0.149 Hom.: 2427

Bravo AF: 0.117

Asia WGS AF: 0.0750 AC: 260 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.166

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.27
DANN	Benign	0.35
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs2230493; hg19: chr3-53213657; COSMIC: COSV104636409;