rs2236379

chr10-6485181-G-Achr10-6485181-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_006257.5(PRKCQ):c.989C>T(p.Pro330Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,612,426 control chromosomes in the GnomAD database, including 65,086 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7246 hom., cov: 31)
  • Exomes 𝑓: 0.27 (57840 hom.)
• Consequence: PRKCQ NM_006257.5 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 0.729

Genes affected

PRKCQ (HGNC:9410): (protein kinase C theta) 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. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipid-dependent protein kinase. This kinase is important for T-cell activation. It is required for the activation of the transcription factors NF-kappaB and AP-1, and may link the T cell receptor (TCR) signaling complex to the activation of the transcription factors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PRKCQ
• BP4: Computational evidence support a benign effect (MetaRNN=8.043051E-4).
• BP6: Variant 10-6485181-G-A is Benign according to our data. Variant chr10-6485181-G-A is described in ClinVar as [Benign]. Clinvar id is 586982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCQ	NM_006257.5	c.989C>T	p.Pro330Leu	missense_variant	10/18	ENST00000263125.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCQ	ENST00000263125.10	c.989C>T	p.Pro330Leu	missense_variant	10/18	1	NM_006257.5	P1
PRKCQ	ENST00000397176.6	c.989C>T	p.Pro330Leu	missense_variant	10/17	5
PRKCQ	ENST00000539722.5	c.614C>T	p.Pro205Leu	missense_variant	9/17	2

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45614 AN: 151740 Hom.: 7250 Cov.: 31

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.305 AC: 76764 AN: 251410 Hom.: 12789 AF XY: 0.305 AC XY: 41410 AN XY: 135870

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.414

Gnomad SAS exome AF: 0.432

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.274 AC: 400411 AN: 1460568 Hom.: 57840 Cov.: 33 AF XY: 0.277 AC XY: 201607 AN XY: 726630

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.378

Gnomad4 ASJ exome AF: 0.255

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.431

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.300 AC: 45628 AN: 151858 Hom.: 7246 Cov.: 31 AF XY: 0.302 AC XY: 22403 AN XY: 74210

Gnomad4 AFR AF: 0.363

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.421

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.295

Alfa AF: 0.269 Hom.: 10942

Bravo AF: 0.313

TwinsUK AF: 0.244 AC: 905

ALSPAC AF: 0.259 AC: 1000

ESP6500AA AF: 0.348 AC: 1535

ESP6500EA AF: 0.250 AC: 2147

ExAC AF: 0.305 AC: 36980

Asia WGS AF: 0.407 AC: 1418 AN: 3478

EpiCase AF: 0.262

EpiControl AF: 0.260

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inflammatory bowel disease 1 Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Lab of Gastroenterology, College of Medicine, First Affiliate Hospital of Zhejiang University

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2020

This variant is associated with the following publications: (PMID: 30828974) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	2.2
Dann	Benign	0.32
DEOGEN2	Benign	0.013	T;T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.76	T;T;T;T
MetaRNN	Benign	0.00080	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.034
MPC		0.47
ClinPred		0.0026	T
GERP RS		-2.7
Varity_R		0.026
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2236379; hg19: chr10-6527143; COSMIC: COSV54105779;