3-53179675-G-C

Variant names:

• chr3-53179675-G-C
• rs151061939
• NM_006254.4:c.214G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006254.4(PRKCD):​c.214G>C​(p.Val72Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000939 in 1,613,104 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V72M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.65
• Publications: 3 publications found

Genes affected

PRKCD (HGNC:9399): (protein kinase C delta) The protein encoded by this gene is a member of the protein kinase C family of serine- and threonine-specific protein kinases. The encoded protein is activated by diacylglycerol and is both a tumor suppressor and a positive regulator of cell cycle progression. Also, this protein can positively or negatively regulate apoptosis. Defects in this gene are a cause of autoimmune lymphoproliferative syndrome. [provided by RefSeq, Aug 2017]

PRKCD Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal systemic lupus erythematosus type 16

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008240163).
• BP6: Variant 3-53179675-G-C is Benign according to our data. Variant chr3-53179675-G-C is described in ClinVar as Benign. ClinVar VariationId is 474768.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 = 0.00503 (766/152346) while in subpopulation AFR AF = 0.0175 (728/41580). AF 95% confidence interval is 0.0165. There are 7 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006254.4. 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
	PRKCD	NM_006254.4	MANE Select	c.214G>C	p.Val72Leu	missense	Exon 4 of 19	NP_006245.2
	PRKCD	NM_001354676.2		c.271G>C	p.Val91Leu	missense	Exon 3 of 18	NP_001341605.1
	PRKCD	NM_001354678.2		c.262G>C	p.Val88Leu	missense	Exon 3 of 18	NP_001341607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCD	ENST00000330452.8	TSL:1 MANE Select	c.214G>C	p.Val72Leu	missense	Exon 4 of 19	ENSP00000331602.3	Q05655-1
	PRKCD	ENST00000394729.6	TSL:1	c.214G>C	p.Val72Leu	missense	Exon 3 of 18	ENSP00000378217.2	Q05655-1
	PRKCD	ENST00000949465.1		c.214G>C	p.Val72Leu	missense	Exon 3 of 18	ENSP00000619524.1

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 763 AN: 152228 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00130 AC: 322 AN: 248596 AF XY: 0.000981

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000698

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000512 AC: 748 AN: 1460758 Hom.: 7 Cov.: 45 AF XY: 0.000475 AC XY: 345 AN XY: 726546

African (AFR) AF: 0.0189 AC: 632 AN: 33448

American (AMR) AF: 0.000851 AC: 38 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111460

Other (OTH) AF: 0.00108 AC: 65 AN: 60350

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152346 Hom.: 7 Cov.: 33 AF XY: 0.00469 AC XY: 349 AN XY: 74490

African (AFR) AF: 0.0175 AC: 728 AN: 41580

American (AMR) AF: 0.00163 AC: 25 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.00589

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00161 AC: 196

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.57	N
PhyloP100		3.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Benign	0.27	T
Polyphen		0.0040	B
Vest4		0.30
MutPred		0.47		Gain of sheet (P = 0.0827)
MVP		0.73
MPC		0.79
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.37
gMVP		0.68
Mutation Taster		=90/10	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: rs151061939; hg19: chr3-53213691;