chr3-53178466-G-C

Position:

• chr3-53178466-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BS1_Supporting

The NM_006254.4(PRKCD):​c.44G>C​(p.Gly15Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000685 (10/1460604) while in subpopulation AMR AF= 0.000224 (10/44714). AF 95% confidence interval is 0.000121. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCD	NM_006254.4	c.44G>C	p.Gly15Ala	missense_variant	3/19	ENST00000330452.8	NP_006245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCD	ENST00000330452.8	c.44G>C	p.Gly15Ala	missense_variant	3/19	1	NM_006254.4	ENSP00000331602.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250836 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460604 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

This sequence change replaces glycine with alanine at codon 15 of the PRKCD protein (p.Gly15Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs369358922, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with PRKCD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T;T;T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.5	.;M;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D;N;N;D;N
REVEL	Uncertain	0.50
Sift	Benign	0.091	T;T;T;T;T
Sift4G	Uncertain	0.0090	D;T;T;D;T
Polyphen		0.99, 1.0	.;D;D;.;D
Vest4		0.54, 0.54
MVP		0.87
MPC		2.0
ClinPred		0.57	D
GERP RS		4.1
Varity_R		0.45
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs369358922; hg19: chr3-53212482;