NM_006255.5:c.59T>C

Variant names:

• chr14-61322160-T-C
• NM_006255.5:c.59T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006255.5(PRKCH):​c.59T>C​(p.Val20Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRKCH NM_006255.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01
• Publications: 0 publications found

Genes affected

PRKCH (HGNC:9403): (protein kinase C eta) 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. It is a calcium-independent and phospholipids-dependent protein kinase. It is predominantly expressed in epithelial tissues and has been shown to reside specifically in the cell nucleus. This protein kinase can regulate keratinocyte differentiation by activating the MAP kinase MAPK13 (p38delta)-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha (CEBPA). It is also found to mediate the transcription activation of the transglutaminase 1 (TGM1) gene. Mutations in this gene are associated with susceptibility to cerebral infarction. [provided by RefSeq, Sep 2015]

PRKCH-AS1 (HGNC:55588): (PRKCH antisense RNA 1)

ENSG00000310561 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3134417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCH	NM_006255.5	c.59T>C	p.Val20Ala	missense_variant	Exon 1 of 14	ENST00000332981.11	NP_006246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCH	ENST00000332981.11	c.59T>C	p.Val20Ala	missense_variant	Exon 1 of 14	1	NM_006255.5	ENSP00000329127.5
ENSG00000310561	ENST00000850887.1	c.*126T>C		downstream_gene_variant				ENSP00000520963.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59T>C (p.V20A) alteration is located in exon 1 (coding exon 1) of the PRKCH gene. This alteration results from a T to C substitution at nucleotide position 59, causing the valine (V) at amino acid position 20 to be replaced by an alanine (A). 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	0.12
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.058	T;T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.0	.;M
PhyloP100		5.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.092
Sift	Benign	0.33	T;T
Sift4G	Uncertain	0.010	D;T
Polyphen		0.055	.;B
Vest4		0.23
MutPred		0.44		Loss of MoRF binding (P = 0.1029);Loss of MoRF binding (P = 0.1029);
MVP		0.59
MPC		1.2
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.45
Mutation Taster		=22/78	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: chr14-61788878;