19-53882566-C-T

Variant names:

• chr19-53882566-C-T
• rs2547362
• NM_002739.5:c.72C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002739.5(PRKCG):​c.72C>T​(p.Ala24Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,614,066 control chromosomes in the GnomAD database, including 730,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62102 hom., cov: 31)
  • Exomes 𝑓: 0.96 (668192 hom.)
• Consequence: PRKCG NM_002739.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-53882566-C-T is Benign according to our data. Variant chr19-53882566-C-T is described in ClinVar as [Benign]. Clinvar id is 130037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-53882566-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5	c.72C>T	p.Ala24Ala	synonymous_variant	Exon 1 of 18	ENST00000263431.4	NP_002730.1
PRKCG	NM_001316329.2	c.72C>T	p.Ala24Ala	synonymous_variant	Exon 1 of 19		NP_001303258.1
PRKCG	XM_047439092.1	c.-313C>T		5_prime_UTR_variant	Exon 2 of 20		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4	c.72C>T	p.Ala24Ala	synonymous_variant	Exon 1 of 18	1	NM_002739.5	ENSP00000263431.3

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136490 AN: 152074 Hom.: 62072 Cov.: 31

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.978

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.946

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.957

Gnomad OTH AF: 0.899

GnomAD3 exomes AF: 0.950 AC: 238694 AN: 251208 Hom.: 113857 AF XY: 0.955 AC XY: 129836 AN XY: 135888

Gnomad AFR exome AF: 0.729

Gnomad AMR exome AF: 0.964

Gnomad ASJ exome AF: 0.943

Gnomad EAS exome AF: 0.989

Gnomad SAS exome AF: 0.992

Gnomad FIN exome AF: 0.965

Gnomad NFE exome AF: 0.958

Gnomad OTH exome AF: 0.951

GnomAD4 exome AF: 0.955 AC: 1396639 AN: 1461874 Hom.: 668192 Cov.: 75 AF XY: 0.957 AC XY: 696104 AN XY: 727242

Gnomad4 AFR exome AF: 0.731

Gnomad4 AMR exome AF: 0.960

Gnomad4 ASJ exome AF: 0.944

Gnomad4 EAS exome AF: 0.994

Gnomad4 SAS exome AF: 0.991

Gnomad4 FIN exome AF: 0.963

Gnomad4 NFE exome AF: 0.958

Gnomad4 OTH exome AF: 0.947

GnomAD4 genome AF: 0.897 AC: 136579 AN: 152192 Hom.: 62102 Cov.: 31 AF XY: 0.900 AC XY: 66964 AN XY: 74402

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.943

Gnomad4 ASJ AF: 0.946

Gnomad4 EAS AF: 0.989

Gnomad4 SAS AF: 0.994

Gnomad4 FIN AF: 0.963

Gnomad4 NFE AF: 0.957

Gnomad4 OTH AF: 0.900

Alfa AF: 0.933 Hom.: 36891

Bravo AF: 0.888

Asia WGS AF: 0.962 AC: 3345 AN: 3478

EpiCase AF: 0.961

EpiControl AF: 0.962

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 14 Benign:5

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs2547362; hg19: chr19-54385820;