chr14-61322429-C-T

Variant names:

• chr14-61322429-C-T
• rs778135822
• NM_006255.5:c.328C>T

Variant summary

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

The NM_006255.5(PRKCH):​c.328C>T​(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PRKCH NM_006255.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• 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)

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=0.38665634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCH	NM_006255.5	c.328C>T	p.Arg110Cys	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.328C>T	p.Arg110Cys	missense_variant	Exon 1 of 14	1	NM_006255.5	ENSP00000329127.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445972 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715546

⚠️ 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: 33194

American (AMR) AF: 0.00 AC: 0 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.00 AC: 0 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099210

Other (OTH) AF: 0.00 AC: 0 AN: 59584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328C>T (p.R110C) alteration is located in exon 1 (coding exon 1) of the PRKCH gene. This alteration results from a C to T substitution at nucleotide position 328, causing the arginine (R) at amino acid position 110 to be replaced by a cysteine (C). 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	0.10
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.90	.;L
PhyloP100		2.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D;N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	.;D
Vest4		0.41
MutPred		0.52		Loss of disorder (P = 0.0562);Loss of disorder (P = 0.0562);
MVP		0.51
MPC		0.99
ClinPred		0.98	D
GERP RS		4.8
PromoterAI		-0.072	Neutral
Varity_R		0.37
gMVP		0.48
Mutation Taster		=48/52	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

dbSNP: rs778135822; hg19: chr14-61789147;