chr1-2173976-C-T

Variant names:

• chr1-2173976-C-T
• rs113812918
• NM_002744.6:c.1365C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002744.6(PRKCZ):​c.1365C>T​(p.Thr455Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,612,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: PRKCZ NM_002744.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.52
• Publications: 1 publications found

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 1-2173976-C-T is Benign according to our data. Variant chr1-2173976-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2638074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BS2: High AC in GnomAd4 at 77 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002744.6. 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
	PRKCZ	NM_002744.6	MANE Select	c.1365C>T	p.Thr455Thr	synonymous	Exon 14 of 18	NP_002735.3
	PRKCZ	NM_001242874.3		c.1053C>T	p.Thr351Thr	synonymous	Exon 11 of 15	NP_001229803.1	Q05513-3
	PRKCZ	NM_001350803.2		c.840C>T	p.Thr280Thr	synonymous	Exon 11 of 15	NP_001337732.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCZ	ENST00000378567.8	TSL:1 MANE Select	c.1365C>T	p.Thr455Thr	synonymous	Exon 14 of 18	ENSP00000367830.3	Q05513-1
	PRKCZ	ENST00000400921.6	TSL:1	c.816C>T	p.Thr272Thr	synonymous	Exon 11 of 15	ENSP00000383712.2	Q05513-2
	PRKCZ	ENST00000965048.1		c.1638C>T	p.Thr546Thr	synonymous	Exon 15 of 19	ENSP00000635107.1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000649 AC: 162 AN: 249602 AF XY: 0.000615

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000441

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000848

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000676 AC: 988 AN: 1460474 Hom.: 1 Cov.: 30 AF XY: 0.000659 AC XY: 479 AN XY: 726478

African (AFR) AF: 0.000329 AC: 11 AN: 33424

American (AMR) AF: 0.000427 AC: 19 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00357 AC: 93 AN: 26082

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39574

South Asian (SAS) AF: 0.0000931 AC: 8 AN: 85928

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53386

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5758

European-Non Finnish (NFE) AF: 0.000698 AC: 776 AN: 1111460

Other (OTH) AF: 0.000978 AC: 59 AN: 60332

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74474

African (AFR) AF: 0.000289 AC: 12 AN: 41560

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.000555

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00137

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.79
DANN	Benign	0.76
PhyloP100		-3.5
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs113812918; hg19: chr1-2105415; COSMIC: COSV66068457; COSMIC: COSV66068457;