3-53179675-G-C

Position:

• chr3-53179675-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006254.4(PRKCD):​c.214G>C​(p.Val72Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000939 in 1,613,104 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -19 ACMG points.

• 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=0.008240163).
• BP6: Variant 3-53179675-G-C is Benign according to our data. Variant chr3-53179675-G-C is described in ClinVar as [Benign]. Clinvar id is 474768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00503 (766/152346) while in subpopulation AFR AF= 0.0175 (728/41580). AF 95% confidence interval is 0.0165. There are 7 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCD	NM_006254.4	c.214G>C	p.Val72Leu	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>C	p.Val72Leu	missense_variant	4/19	1	NM_006254.4	ENSP00000331602.3

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 763 AN: 152228 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00130 AC: 322 AN: 248596 Hom.: 4 AF XY: 0.000981 AC XY: 132 AN XY: 134488

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000698

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000512 AC: 748 AN: 1460758 Hom.: 7 Cov.: 45 AF XY: 0.000475 AC XY: 345 AN XY: 726546

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.000851

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152346 Hom.: 7 Cov.: 33 AF XY: 0.00469 AC XY: 349 AN XY: 74490

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.00589

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00161 AC: 196

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.039	T;T;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T;.;D;D;D
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.57	.;N;N;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.0040, 0.0050	.;B;B;.;B
Vest4		0.30, 0.30
MutPred		0.47		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.73
MPC		0.79
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.37
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;