chr1-2055515-G-A

Position:

• chr1-2055515-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002744.6(PRKCZ):​c.146G>A​(p.Arg49His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,060 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0077 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (17 hom.)
• Consequence: PRKCZ NM_002744.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.12

Genes affected

PRKCZ (HGNC:9412): (protein kinase C zeta) Protein kinase C (PKC) zeta is a member of the PKC family of serine/threonine kinases which are involved in a variety of cellular processes such as proliferation, differentiation and secretion. Unlike the classical PKC isoenzymes which are calcium-dependent, PKC zeta exhibits a kinase activity which is independent of calcium and diacylglycerol but not of phosphatidylserine. Furthermore, it is insensitive to typical PKC inhibitors and cannot be activated by phorbol ester. Unlike the classical PKC isoenzymes, it has only a single zinc finger module. These structural and biochemical properties indicate that the zeta subspecies is related to, but distinct from other isoenzymes of PKC. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041430593).
• BP6: Variant 1-2055515-G-A is Benign according to our data. Variant chr1-2055515-G-A is described in ClinVar as [Benign]. Clinvar id is 714063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00772 (1175/152284) while in subpopulation AFR AF= 0.0269 (1119/41548). AF 95% confidence interval is 0.0256. There are 14 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCZ	NM_002744.6	c.146G>A	p.Arg49His	missense_variant	2/18	ENST00000378567.8	NP_002735.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCZ	ENST00000378567.8	c.146G>A	p.Arg49His	missense_variant	2/18	1	NM_002744.6	ENSP00000367830	P1

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1158 AN: 152166 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00184 AC: 462 AN: 251096 Hom.: 5 AF XY: 0.00133 AC XY: 181 AN XY: 135830

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000815 AC: 1191 AN: 1461776 Hom.: 17 Cov.: 30 AF XY: 0.000716 AC XY: 521 AN XY: 727186

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00772 AC: 1175 AN: 152284 Hom.: 14 Cov.: 32 AF XY: 0.00753 AC XY: 561 AN XY: 74460

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000611 Hom.: 0

Bravo AF: 0.00868

ESP6500AA AF: 0.0213 AC: 94

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.18	T;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.60	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.22
MVP		0.68
MPC		0.30
ClinPred		0.011	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35271800; hg19: chr1-1986954;