NM_002737.3:c.388A>G

Variant names:

• chr17-66641454-A-G
• NM_002737.3:c.388A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002737.3(PRKCA):​c.388A>G​(p.Met130Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• 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 2 ACMG points.

• 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.388A>G	p.Met130Val	missense_variant	Exon 4 of 17	ENST00000413366.8	NP_002728.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCA	ENST00000413366.8	c.388A>G	p.Met130Val	missense_variant	Exon 4 of 17	1	NM_002737.3	ENSP00000408695.3
PRKCA	ENST00000578063.5	n.388A>G		non_coding_transcript_exon_variant	Exon 4 of 10	1		ENSP00000462087.1
PRKCA	ENST00000284384.6	n.440A>G		non_coding_transcript_exon_variant	Exon 5 of 15	5		ENSP00000284384.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454508 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723474

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 84890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107254

Other (OTH) AF: 0.00 AC: 0 AN: 60098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.005537), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388A>G (p.M130V) alteration is located in exon 4 (coding exon 4) of the PRKCA gene. This alteration results from a A to G substitution at nucleotide position 388, causing the methionine (M) at amino acid position 130 to be replaced by a valine (V). 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	0.22
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.037
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Benign	0.42	N
PhyloP100		8.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.59
Sift	Benign	0.24	T
Sift4G	Benign	0.17	T
Polyphen		0.016	B
Vest4		0.79
MutPred		0.59		Gain of loop (P = 0.0195);
MVP		0.99
MPC		1.5
ClinPred		0.68	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.63
Mutation Taster		=58/42	polymorphism

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: chr17-64637572;