3-170293378-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002740.6(PRKCI):c.1292-5T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,600,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: PRKCI NM_002740.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01379
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0500

Genes affected

PRKCI (HGNC:9404): (protein kinase C iota) This gene encodes a member of the protein kinase C (PKC) family of serine/threonine protein kinases. The PKC family comprises at least eight members, which are differentially expressed and are involved in a wide variety of cellular processes. This protein kinase is calcium-independent and phospholipid-dependent. It is not activated by phorbolesters or diacylglycerol. This kinase can be recruited to vesicle tubular clusters (VTCs) by direct interaction with the small GTPase RAB2, where this kinase phosphorylates glyceraldehyde-3-phosphate dehydrogenase (GAPD/GAPDH) and plays a role in microtubule dynamics in the early secretory pathway. This kinase is found to be necessary for BCL-ABL-mediated resistance to drug-induced apoptosis and therefore protects leukemia cells against drug-induced apoptosis. There is a single exon pseudogene mapped on chromosome X. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-170293378-T-G is Benign according to our data. Variant chr3-170293378-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3049278.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCI	NM_002740.6	c.1292-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000295797.5
PRKCI	XM_047448574.1	c.1204-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PRKCI	XM_047448575.1	c.950-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCI	ENST00000295797.5	c.1292-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002740.6	P1
PRKCI	ENST00000476635.5	n.301-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
PRKCI	ENST00000483697.2	n.32T>G		non_coding_transcript_exon_variant	1/3	3
PRKCI	ENST00000485837.5	n.47T>G		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000449 AC: 106 AN: 236306 Hom.: 0 AF XY: 0.000446 AC XY: 57 AN XY: 127720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000968

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.000324 AC: 470 AN: 1448510 Hom.: 1 Cov.: 30 AF XY: 0.000347 AC XY: 250 AN XY: 720350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000883

Gnomad4 ASJ exome AF: 0.00423

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000270

Gnomad4 OTH exome AF: 0.000451

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74340

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000605 Hom.: 0

Bravo AF: 0.000423

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRKCI-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.5
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.35
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: rs200153796; hg19: chr3-170011166;