3-170270533-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002740.6(PRKCI):c.563T>C(p.Ile188Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PRKCI NM_002740.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039138794).
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCI	NM_002740.6	c.563T>C	p.Ile188Thr	missense_variant	6/18	ENST00000295797.5
PRKCI	XM_047448575.1	c.221T>C	p.Ile74Thr	missense_variant	5/17
PRKCI	XM_047448574.1	c.563T>C	p.Ile188Thr	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCI	ENST00000295797.5	c.563T>C	p.Ile188Thr	missense_variant	6/18	1	NM_002740.6	P1

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 151776 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000996 AC: 25 AN: 250958 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135718

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000116

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: 0.0000294 AC: 43 AN: 1461154 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 726906

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000134

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000316 AC: 48 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74234

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000913 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.563T>C (p.I188T) alteration is located in exon 6 (coding exon 6) of the PRKCI gene. This alteration results from a T to C substitution at nucleotide position 563, causing the isoleucine (I) at amino acid position 188 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	16
Dann	Benign	0.33
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.32	N
MutationTaster	Benign	0.74	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.33
Sift	Benign	0.74	T
Sift4G	Benign	0.50	T
Polyphen		0.12	B
Vest4		0.26
MVP		0.98
MPC		0.89
ClinPred		0.013	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147562215; hg19: chr3-169988321;