3-53178490-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_006254.4(PRKCD):c.68C>T(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A23A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.467

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_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKCD
• BP4: Computational evidence support a benign effect (MetaRNN=0.012200296).
• BP6: Variant 3-53178490-C-T is Benign according to our data. Variant chr3-53178490-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 660963.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000394 (60/152342) while in subpopulation AMR AF= 0.000915 (14/15304). AF 95% confidence interval is 0.000552. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCD	NM_006254.4	c.68C>T	p.Ala23Val	missense_variant	3/19	ENST00000330452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCD	ENST00000330452.8	c.68C>T	p.Ala23Val	missense_variant	3/19	1	NM_006254.4	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 250858 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135772

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1460802 Hom.: 0 Cov.: 31 AF XY: 0.000169 AC XY: 123 AN XY: 726698

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000362 AC XY: 27 AN XY: 74492

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000273 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.68C>T (p.A23V) alteration is located in exon 3 (coding exon 1) of the PRKCD gene. This alteration results from a C to T substitution at nucleotide position 68, causing the alanine (A) at amino acid position 23 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	10
Dann	Benign	0.82
DEOGEN2	Benign	0.018	T;T;T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.56	T;.;T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;.;B
Vest4		0.19, 0.19
MVP		0.82
MPC		0.79
ClinPred		0.0013	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.20
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144572650; hg19: chr3-53212506;