17-66687137-A-C

Variant names:

• chr17-66687137-A-C
• NM_002737.3:c.556A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002737.3(PRKCA):​c.556A>C​(p.Met186Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M186V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKCA NM_002737.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

PRKCA (HGNC:9393): (protein kinase C alpha) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been reported to play roles in many different cellular processes, such as cell adhesion, cell transformation, cell cycle checkpoint, and cell volume control. Knockout studies in mice suggest that this kinase may be a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity KPCA_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCA	NM_002737.3	c.556A>C	p.Met186Leu	missense_variant	Exon 6 of 17	ENST00000413366.8	NP_002728.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCA	ENST00000413366.8	c.556A>C	p.Met186Leu	missense_variant	Exon 6 of 17	1	NM_002737.3	ENSP00000408695.3
PRKCA	ENST00000578063.5	n.556A>C		non_coding_transcript_exon_variant	Exon 6 of 10	1		ENSP00000462087.1
PRKCA	ENST00000284384.6	n.*158A>C		non_coding_transcript_exon_variant	Exon 7 of 15	5		ENSP00000284384.6
PRKCA	ENST00000284384.6	n.*158A>C		3_prime_UTR_variant	Exon 7 of 15	5		ENSP00000284384.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556A>C (p.M186L) alteration is located in exon 6 (coding exon 6) of the PRKCA gene. This alteration results from a A to C substitution at nucleotide position 556, causing the methionine (M) at amino acid position 186 to be replaced by a leucine (L). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.0	L
PhyloP100		8.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.028	D
Sift4G	Benign	0.20	T
Polyphen		0.16	B
Vest4		0.54
MutPred		0.58		Loss of ubiquitination at K181 (P = 0.1828);
MVP		0.93
MPC		0.83
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.47

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: chr17-64683255;