chr1-2150880-C-T

Position:

• chr1-2150880-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002744.6(PRKCZ):​c.778C>T​(p.Arg260Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKCZ NM_002744.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKCZ	NM_002744.6	c.778C>T	p.Arg260Cys	missense_variant	9/18	ENST00000378567.8	NP_002735.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKCZ	ENST00000378567.8	c.778C>T	p.Arg260Cys	missense_variant	9/18	1	NM_002744.6	ENSP00000367830	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Mar 06, 2018

This variant was identified in a 12 year old male with mild intellectual disability, motor speech disorder, adaptive deficits, dyspraxia, hypotonia, ADHD, bifid uvula, mild dolichocephaly, large ears, mild pectus excavatum, hypoplastic nipples, and slightly tapered fingers. The variant is absent from the gnomAD database, and it was found to be de novo (with maternity and paternity confirmed). Computational prediction models are inconsistent. This is a gene of uncertain significance; no known human disorders have been clearly associated with this gene. The gene is not constrained for missense or loss of function variants, and deletions are reported in the Database of Genomic Variation. Additionally, whole exome sequencing also identified two additional variants of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;.;.;T;T;.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;T;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.84
MutPred		0.74		Loss of methylation at R260 (P = 0.008);.;.;.;.;.;.;.;
MVP		0.91
MPC		2.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs887317345; hg19: chr1-2082319; COSMIC: COSV66066195; COSMIC: COSV66066195;