chr3-170284492-A-G

Variant names:

• chr3-170284492-A-G
• NM_002740.6:c.1099A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002740.6(PRKCI):​c.1099A>G​(p.Asn367Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCI NM_002740.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCI	NM_002740.6	c.1099A>G	p.Asn367Asp	missense_variant	Exon 12 of 18	ENST00000295797.5	NP_002731.4
PRKCI	XM_047448575.1	c.757A>G	p.Asn253Asp	missense_variant	Exon 11 of 17		XP_047304531.1
PRKCI	XM_047448574.1	c.1099A>G	p.Asn367Asp	missense_variant	Exon 12 of 13		XP_047304530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCI	ENST00000295797.5	c.1099A>G	p.Asn367Asp	missense_variant	Exon 12 of 18	1	NM_002740.6	ENSP00000295797.4
PRKCI	ENST00000482353.2	n.391A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1099A>G (p.N367D) alteration is located in exon 12 (coding exon 12) of the PRKCI gene. This alteration results from a A to G substitution at nucleotide position 1099, causing the asparagine (N) at amino acid position 367 to be replaced by an aspartic acid (D). 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	Uncertain	0.56
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.20	N
PhyloP100		8.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.028	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.34		Gain of relative solvent accessibility (P = 0.09);
MVP		0.83
MPC		0.90
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.74
Mutation Taster		=26/74	disease causing

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

Other links and lift over

hg19: chr3-170002280;