NM_006254.4:c.1782C>G

Variant names:

• chr3-53189911-C-G
• rs1075865
• NM_006254.4:c.1782C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006254.4(PRKCD):​c.1782C>G​(p.Thr594Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.983 in 1,614,192 control chromosomes in the GnomAD database, including 781,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67685 hom., cov: 32)
  • Exomes 𝑓: 0.99 (713326 hom.)
• Consequence: PRKCD NM_006254.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.683
• Publications: 20 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):

• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-53189911-C-G is Benign according to our data. Variant chr3-53189911-C-G is described in ClinVar as Benign. ClinVar VariationId is 403347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.683 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCD	NM_006254.4	MANE Select	c.1782C>G	p.Thr594Thr	synonymous	Exon 18 of 19	NP_006245.2
	PRKCD	NM_001354676.2		c.1839C>G	p.Thr613Thr	synonymous	Exon 17 of 18	NP_001341605.1
	PRKCD	NM_001354678.2		c.1830C>G	p.Thr610Thr	synonymous	Exon 17 of 18	NP_001341607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKCD	ENST00000330452.8	TSL:1 MANE Select	c.1782C>G	p.Thr594Thr	synonymous	Exon 18 of 19	ENSP00000331602.3
	PRKCD	ENST00000394729.6	TSL:1	c.1782C>G	p.Thr594Thr	synonymous	Exon 17 of 18	ENSP00000378217.2
	PRKCD	ENST00000650739.1		c.1782C>G	p.Thr594Thr	synonymous	Exon 18 of 19	ENSP00000498623.1

Frequencies

GnomAD3 genomes AF: 0.939 AC: 142940 AN: 152190 Hom.: 67649 Cov.: 32

Gnomad AFR AF: 0.805

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.895

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.952

GnomAD2 exomes AF: 0.970 AC: 243909 AN: 251488 AF XY: 0.969

Gnomad AFR exome AF: 0.802

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 0.968

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.987

GnomAD4 exome AF: 0.987 AC: 1443054 AN: 1461884 Hom.: 713326 Cov.: 61 AF XY: 0.985 AC XY: 716504 AN XY: 727242

African (AFR) AF: 0.804 AC: 26917 AN: 33480

American (AMR) AF: 0.989 AC: 44239 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26109 AN: 26136

East Asian (EAS) AF: 0.976 AC: 38750 AN: 39698

South Asian (SAS) AF: 0.900 AC: 77619 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53416 AN: 53416

Middle Eastern (MID) AF: 0.984 AC: 5675 AN: 5768

European-Non Finnish (NFE) AF: 0.999 AC: 1111243 AN: 1112010

Other (OTH) AF: 0.978 AC: 59086 AN: 60394

GnomAD4 genome AF: 0.939 AC: 143032 AN: 152308 Hom.: 67685 Cov.: 32 AF XY: 0.940 AC XY: 69979 AN XY: 74472

African (AFR) AF: 0.805 AC: 33426 AN: 41528

American (AMR) AF: 0.978 AC: 14964 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3469 AN: 3472

East Asian (EAS) AF: 0.972 AC: 5044 AN: 5190

South Asian (SAS) AF: 0.895 AC: 4319 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67969 AN: 68042

Other (OTH) AF: 0.953 AC: 2014 AN: 2114

Alfa AF: 0.950 Hom.: 17764

Bravo AF: 0.934

Asia WGS AF: 0.913 AC: 3177 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions as Germline

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)
-	-	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.23
DANN	Benign	0.61
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs1075865; hg19: chr3-53223927; COSMIC: COSV108148446; COSMIC: COSV108148446;