chr3-53178466-G-C

Variant names:

• chr3-53178466-G-C
• rs369358922
• NM_006254.4:c.44G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_006254.4(PRKCD):​c.44G>C​(p.Gly15Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G15D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000685 (10/1460604) while in subpopulation AMR AF = 0.000224 (10/44714). AF 95% confidence interval is 0.000121. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.44G>C	p.Gly15Ala	missense	Exon 3 of 19	NP_006245.2
	PRKCD	NM_001354676.2		c.101G>C	p.Gly34Ala	missense	Exon 2 of 18	NP_001341605.1
	PRKCD	NM_001354678.2		c.92G>C	p.Gly31Ala	missense	Exon 2 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.44G>C	p.Gly15Ala	missense	Exon 3 of 19	ENSP00000331602.3	Q05655-1
	PRKCD	ENST00000394729.6	TSL:1	c.44G>C	p.Gly15Ala	missense	Exon 2 of 18	ENSP00000378217.2	Q05655-1
	PRKCD	ENST00000949465.1		c.44G>C	p.Gly15Ala	missense	Exon 2 of 18	ENSP00000619524.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250836 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

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: 0.00000685 AC: 10 AN: 1460604 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726600

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000224 AC: 10 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.50
Sift	Benign	0.091	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.54
MVP		0.87
MPC		2.0
ClinPred		0.57	D
GERP RS		4.1
Varity_R		0.45
gMVP		0.70
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs369358922; hg19: chr3-53212482;