1-2172067-C-G

Variant names:

• chr1-2172067-C-G
• rs2280272
• NM_002744.6:c.1074C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_002744.6(PRKCZ):​c.1074C>G​(p.Ala358Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,609,038 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (152 hom.)
• Consequence: PRKCZ NM_002744.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B: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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-2172067-C-G is Benign according to our data. Variant chr1-2172067-C-G is described in ClinVar as [Benign]. Clinvar id is 718957.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCZ	NM_002744.6	c.1074C>G	p.Ala358Ala	synonymous_variant	Exon 12 of 18	ENST00000378567.8	NP_002735.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCZ	ENST00000378567.8	c.1074C>G	p.Ala358Ala	synonymous_variant	Exon 12 of 18	1	NM_002744.6	ENSP00000367830.3

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 152216 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00764 AC: 1881 AN: 246284 AF XY: 0.00717

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00167

Gnomad EAS exome AF: 0.0830

Gnomad FIN exome AF: 0.00451

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.00584

GnomAD4 exome AF: 0.00325 AC: 4732 AN: 1456704 Hom.: 152 Cov.: 32 AF XY: 0.00326 AC XY: 2359 AN XY: 724382

Gnomad4 AFR exome AF: 0.000299 AC: 10 AN: 33390

Gnomad4 AMR exome AF: 0.000293 AC: 13 AN: 44382

Gnomad4 ASJ exome AF: 0.00210 AC: 54 AN: 25684

Gnomad4 EAS exome AF: 0.0821 AC: 3255 AN: 39662

Gnomad4 SAS exome AF: 0.00427 AC: 365 AN: 85496

Gnomad4 FIN exome AF: 0.00431 AC: 227 AN: 52624

Gnomad4 NFE exome AF: 0.000370 AC: 411 AN: 1109520

Gnomad4 Remaining exome AF: 0.00641 AC: 386 AN: 60208

GnomAD4 genome AF: 0.00382 AC: 582 AN: 152334 Hom.: 18 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74486

Gnomad4 AFR AF: 0.000793 AC: 0.00079346 AN: 0.00079346

Gnomad4 AMR AF: 0.000457 AC: 0.000457457 AN: 0.000457457

Gnomad4 ASJ AF: 0.00115 AC: 0.00115207 AN: 0.00115207

Gnomad4 EAS AF: 0.0817 AC: 0.0816918 AN: 0.0816918

Gnomad4 SAS AF: 0.00663 AC: 0.006628 AN: 0.006628

Gnomad4 FIN AF: 0.00433 AC: 0.00433227 AN: 0.00433227

Gnomad4 NFE AF: 0.000470 AC: 0.000470408 AN: 0.000470408

Gnomad4 OTH AF: 0.00237 AC: 0.00236518 AN: 0.00236518

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00405

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.028
DANN	Benign	0.45
Mutation Taster		=94/6	polymorphism (auto)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2280272; hg19: chr1-2103506; COSMIC: COSV66067651;