rs147040074

Variant names:

• chr10-6430871-C-A
• rs147040074
• NM_006257.5:c.1904G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-6430871-C-A
• chr10-6430871-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006257.5(PRKCQ):​c.1904G>T​(p.Arg635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R635Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRKCQ NM_006257.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1904G>T	p.Arg635Leu	missense	Exon 17 of 18	NP_006248.1	Q04759-1
	PRKCQ	NM_001323265.1		c.1904G>T	p.Arg635Leu	missense	Exon 17 of 18	NP_001310194.1	Q04759-1
	PRKCQ	NM_001282644.2		c.1796G>T	p.Arg599Leu	missense	Exon 17 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.1904G>T	p.Arg635Leu	missense	Exon 17 of 18	ENSP00000263125.5	Q04759-1
	PRKCQ	ENST00000915286.1		c.1928G>T	p.Arg643Leu	missense	Exon 17 of 18	ENSP00000585345.1
	PRKCQ	ENST00000866196.1		c.1904G>T	p.Arg635Leu	missense	Exon 17 of 18	ENSP00000536255.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251376 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.020
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		0.052	B
Vest4		0.59
MutPred		0.47		Loss of disorder (P = 0.0335)
MVP		0.64
MPC		0.60
ClinPred		0.98	D
GERP RS		-0.11
Varity_R		0.38
gMVP		0.67
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147040074; hg19: chr10-6472833; COSMIC: COSV54108767;