10-6464322-G-C

Variant names:

• chr10-6464322-G-C
• rs78855257
• NM_006257.5:c.1436C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 16/21 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0450
• Publications: 4 publications found

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]

ENSG00000302067 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 776493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1063 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006257.5. 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
	PRKCQ	NM_006257.5	MANE Select	c.1436C>G	p.Ser479Cys	missense	Exon 13 of 18	NP_006248.1	Q04759-1
	PRKCQ	NM_001323265.1		c.1436C>G	p.Ser479Cys	missense	Exon 13 of 18	NP_001310194.1	Q04759-1
	PRKCQ	NM_001282644.2		c.1328C>G	p.Ser443Cys	missense	Exon 13 of 18	NP_001269573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCQ	ENST00000263125.10	TSL:1 MANE Select	c.1436C>G	p.Ser479Cys	missense	Exon 13 of 18	ENSP00000263125.5	Q04759-1
	PRKCQ	ENST00000915286.1		c.1436C>G	p.Ser479Cys	missense	Exon 13 of 18	ENSP00000585345.1
	PRKCQ	ENST00000866196.1		c.1436C>G	p.Ser479Cys	missense	Exon 13 of 18	ENSP00000536255.1

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

GnomAD2 exomes AF: 0.00181 AC: 454 AN: 251146 AF XY: 0.00129

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 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

African (AFR) AF: 0.0274 AC: 915 AN: 33414

American (AMR) AF: 0.00101 AC: 45 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111762

Other (OTH) AF: 0.00179 AC: 108 AN: 60378

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

African (AFR) AF: 0.0244 AC: 1016 AN: 41570

American (AMR) AF: 0.00222 AC: 34 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.045
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Benign	0.15	T
Sift4G	Uncertain	0.045	D
Polyphen		0.0	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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs78855257; hg19: chr10-6506284; COSMIC: COSV99036927;