3-53186699-C-T

Position:

• chr3-53186699-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The ENST00000330452.8(PRKCD):​c.1352+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,611,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: PRKCD ENST00000330452.8 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0002905
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.914

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000177 (27/152348) while in subpopulation NFE AF= 0.000265 (18/68034). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 34. 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.1352+4C>T		splice_donor_region_variant, intron_variant		ENST00000330452.8	NP_006245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCD	ENST00000330452.8	c.1352+4C>T		splice_donor_region_variant, intron_variant		1	NM_006254.4	ENSP00000331602	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000192 AC: 48 AN: 249690 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 134968

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000265 AC: 386 AN: 1459254 Hom.: 0 Cov.: 32 AF XY: 0.000278 AC XY: 202 AN XY: 726034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152348 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74488

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000144

EpiCase AF: 0.000492

EpiControl AF: 0.0000594

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

Oct 05, 2022

This sequence change falls in intron 14 of the PRKCD gene. It does not directly change the encoded amino acid sequence of the PRKCD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs202155309, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PRKCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 576675). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.19
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.14		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: rs202155309; hg19: chr3-53220715;