rs2230500

Variant names:

• chr14-61457521-G-A
• rs2230500
• NM_006255.5:c.1120G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006255.5(PRKCH):​c.1120G>A​(p.Val374Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,004 control chromosomes in the GnomAD database, including 1,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.019 (190 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1393 hom.)
• Consequence: PRKCH NM_006255.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.13
• Publications: 48 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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019232929).
• BP6: Variant 14-61457521-G-A is Benign according to our data. Variant chr14-61457521-G-A is described in ClinVar as Benign. ClinVar VariationId is 4991.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006255.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCH	NM_006255.5	MANE Select	c.1120G>A	p.Val374Ile	missense	Exon 9 of 14	NP_006246.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCH	ENST00000332981.11	TSL:1 MANE Select	c.1120G>A	p.Val374Ile	missense	Exon 9 of 14	ENSP00000329127.5	P24723-1
	PRKCH	ENST00000555082.6	TSL:1	c.637G>A	p.Val213Ile	missense	Exon 9 of 14	ENSP00000450981.1	P24723-2
	PRKCH	ENST00000557585.5	TSL:5	c.637G>A	p.Val213Ile	missense	Exon 9 of 9	ENSP00000451930.1	G3V4Q6

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2851 AN: 152116 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0308 AC: 7738 AN: 251296 AF XY: 0.0299

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0180 AC: 26311 AN: 1461768 Hom.: 1393 Cov.: 32 AF XY: 0.0177 AC XY: 12888 AN XY: 727184

African (AFR) AF: 0.00167 AC: 56 AN: 33478

American (AMR) AF: 0.00653 AC: 292 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00911 AC: 238 AN: 26130

East Asian (EAS) AF: 0.242 AC: 9587 AN: 39694

South Asian (SAS) AF: 0.0128 AC: 1108 AN: 86252

European-Finnish (FIN) AF: 0.0322 AC: 1719 AN: 53420

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5766

European-Non Finnish (NFE) AF: 0.0105 AC: 11729 AN: 1111928

Other (OTH) AF: 0.0258 AC: 1557 AN: 60382

GnomAD4 genome AF: 0.0187 AC: 2854 AN: 152236 Hom.: 190 Cov.: 32 AF XY: 0.0211 AC XY: 1568 AN XY: 74428

African (AFR) AF: 0.00233 AC: 97 AN: 41556

American (AMR) AF: 0.00922 AC: 141 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.258 AC: 1328 AN: 5156

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4818

European-Finnish (FIN) AF: 0.0327 AC: 347 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 742 AN: 68008

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0185 Hom.: 383

Bravo AF: 0.0170

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.0294 AC: 3570

Asia WGS AF: 0.135 AC: 468 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00865

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Ischemic stroke (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N
PhyloP100		2.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.064
Sift	Benign	0.30	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.056
MPC		0.41
ClinPred		0.0051	T
GERP RS		4.6
Varity_R		0.062
gMVP		0.14
Mutation Taster		=99/1	polymorphism (auto)

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: rs2230500; hg19: chr14-61924239; COSMIC: COSV60646806; COSMIC: COSV60646806;