19-53884243-C-T

Variant names:

• chr19-53884243-C-T
• rs17854523
• NM_002739.5:c.285C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002739.5(PRKCG):​c.285C>T​(p.Asp95Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,613,684 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (230 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (237 hom.)
• Consequence: PRKCG NM_002739.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.004953
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.272
• Publications: 8 publications found

Genes affected

PRKCG (HGNC:9402): (protein kinase C gamma) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and 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 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 distinct roles in cells. The protein encoded by this gene is one of the PKC family members. This protein kinase is expressed solely in the brain and spinal cord and its localization is restricted to neurons. It has been demonstrated that several neuronal functions, including long term potentiation (LTP) and long term depression (LTD), specifically require this kinase. Knockout studies in mice also suggest that this kinase may be involved in neuropathic pain development. Defects in this protein have been associated with neurodegenerative disorder spinocerebellar ataxia-14 (SCA14). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PRKCG Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 14

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.085).
• BP6: Variant 19-53884243-C-T is Benign according to our data. Variant chr19-53884243-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.272 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5	c.285C>T	p.Asp95Asp	splice_region_variant, synonymous_variant	Exon 3 of 18	ENST00000263431.4	NP_002730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4	c.285C>T	p.Asp95Asp	splice_region_variant, synonymous_variant	Exon 3 of 18	1	NM_002739.5	ENSP00000263431.3

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4737 AN: 152128 Hom.: 229 Cov.: 32

Gnomad AFR AF: 0.0998

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0115 AC: 2887 AN: 251378 AF XY: 0.00918

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0109

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.00493 AC: 7208 AN: 1461438 Hom.: 237 Cov.: 32 AF XY: 0.00457 AC XY: 3323 AN XY: 727012

African (AFR) AF: 0.106 AC: 3539 AN: 33468

American (AMR) AF: 0.0144 AC: 642 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 305 AN: 26136

East Asian (EAS) AF: 0.00564 AC: 224 AN: 39700

South Asian (SAS) AF: 0.00175 AC: 151 AN: 86224

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53410

Middle Eastern (MID) AF: 0.0225 AC: 123 AN: 5468

European-Non Finnish (NFE) AF: 0.00136 AC: 1510 AN: 1111958

Other (OTH) AF: 0.0118 AC: 711 AN: 60350

GnomAD4 genome AF: 0.0312 AC: 4755 AN: 152246 Hom.: 230 Cov.: 32 AF XY: 0.0305 AC XY: 2267 AN XY: 74446

African (AFR) AF: 0.100 AC: 4153 AN: 41538

American (AMR) AF: 0.0167 AC: 255 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5174

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68022

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0130 Hom.: 162

Bravo AF: 0.0358

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 14 Benign:3

Apr 05, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 16, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Uncertain	0.99
PhyloP100		0.27
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0050
dbscSNV1_RF	Benign	0.14
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: rs17854523; hg19: chr19-54387497;