10-6464322-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_006257.5(PRKCQ):c.1436C>G(p.Ser479Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,750 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (13 hom.)
• Consequence: PRKCQ NM_006257.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0450

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=0.0076928735).
• BP6: Variant 10-6464322-G-C is Benign according to our data. Variant chr10-6464322-G-C is described in ClinVar as [Benign]. Clinvar id is 776493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00698 (1063/152320) while in subpopulation AFR AF= 0.0244 (1016/41570). AF 95% confidence interval is 0.0232. There are 16 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1059 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKCQ	NM_006257.5	c.1436C>G	p.Ser479Cys	missense_variant	13/18	ENST00000263125.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKCQ	ENST00000263125.10	c.1436C>G	p.Ser479Cys	missense_variant	13/18	1	NM_006257.5	P1
PRKCQ	ENST00000397176.6	c.1436C>G	p.Ser479Cys	missense_variant	13/17	5
PRKCQ	ENST00000539722.5	c.1061C>G	p.Ser354Cys	missense_variant	12/17	2

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152202 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00181 AC: 454 AN: 251146 Hom.: 7 AF XY: 0.00129 AC XY: 175 AN XY: 135770

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000756 AC: 1105 AN: 1461430 Hom.: 13 Cov.: 31 AF XY: 0.000644 AC XY: 468 AN XY: 727066

Gnomad4 AFR exome AF: 0.0274

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00698 AC: 1063 AN: 152320 Hom.: 16 Cov.: 32 AF XY: 0.00697 AC XY: 519 AN XY: 74484

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000996 Hom.: 0

Bravo AF: 0.00782

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00231 AC: 280

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	15
Dann	Benign	0.74
DEOGEN2	Benign	0.093	T;T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.74	T;T;T;T
MetaRNN	Benign	0.0077	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
Sift4G	Uncertain	0.045	D;T;T;D
Polyphen		0.0	.;B;B;.
Vest4		0.19
MVP		0.70
MPC		0.44
ClinPred		0.0095	T
GERP RS		-2.4
Varity_R		0.15
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78855257; hg19: chr10-6506284; COSMIC: COSV99036927;