chr3-53178490-C-T

Variant names:

• chr3-53178490-C-T
• rs144572650
• NM_006254.4:c.68C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006254.4(PRKCD):​c.68C>T​(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A23A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PRKCD NM_006254.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.467
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012200296).
• BP6: Variant 3-53178490-C-T is Benign according to our data. Variant chr3-53178490-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 660963.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000394 (60/152342) while in subpopulation AMR AF = 0.000915 (14/15304). AF 95% confidence interval is 0.000552. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.68C>T	p.Ala23Val	missense	Exon 3 of 19	NP_006245.2
	PRKCD	NM_001354676.2		c.125C>T	p.Ala42Val	missense	Exon 2 of 18	NP_001341605.1
	PRKCD	NM_001354678.2		c.116C>T	p.Ala39Val	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.68C>T	p.Ala23Val	missense	Exon 3 of 19	ENSP00000331602.3	Q05655-1
	PRKCD	ENST00000394729.6	TSL:1	c.68C>T	p.Ala23Val	missense	Exon 2 of 18	ENSP00000378217.2	Q05655-1
	PRKCD	ENST00000949465.1		c.68C>T	p.Ala23Val	missense	Exon 2 of 18	ENSP00000619524.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 250858 AF XY: 0.000169

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1460802 Hom.: 0 Cov.: 31 AF XY: 0.000169 AC XY: 123 AN XY: 726698

African (AFR) AF: 0.000448 AC: 15 AN: 33448

American (AMR) AF: 0.000201 AC: 9 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86224

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53114

Middle Eastern (MID) AF: 0.00488 AC: 26 AN: 5324

European-Non Finnish (NFE) AF: 0.000156 AC: 174 AN: 1111848

Other (OTH) AF: 0.000265 AC: 16 AN: 60322

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000362 AC XY: 27 AN XY: 74492

African (AFR) AF: 0.000722 AC: 30 AN: 41580

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.82
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.47
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.089
Sift	Benign	0.42	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.82
MPC		0.79
ClinPred		0.0013	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.20
gMVP		0.39
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144572650; hg19: chr3-53212506;