Genetic Variant NM_002739.5:c.1281+9G>A (chr19-53898637-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_002739.5(PRKCG):c.1281+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,409,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

PRKCG
NM_002739.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

0 publications found

Variant links:

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)

PRKCG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PRKCG	NM_002739.5 link	c.1281+9G>A	intron_variant	Intron 11 of 17	ENST00000263431.4	NP_002730.1	P05129-1
PRKCG	NM_001316329.2 link	c.1281+9G>A	intron_variant	Intron 11 of 18		NP_001303258.1	P05129B7Z3W6B2R5T1A0A804HIU5
PRKCG	XM_047439092.1 link	c.897+9G>A	intron_variant	Intron 12 of 19		XP_047295048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCG	ENST00000263431.4 link	c.1281+9G>A		intron_variant	Intron 11 of 17	1	NM_002739.5	ENSP00000263431.3		P05129-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000606

AC:

AN:

165056

AF XY:

0.0000112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000426

AC:

AN:

1409926

Hom.:

Cov.:

AF XY:

0.00000574

AC XY:

AN XY:

697364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31892

American (AMR)

AF:

0.00

AC:

AN:

36840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25304

East Asian (EAS)

AF:

0.00

AC:

AN:

36244

South Asian (SAS)

AF:

0.00

AC:

AN:

81336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.00000552

AC:

AN:

1086734

Other (OTH)

AF:

0.00

AC:

AN:

58346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.7

(source)

DANN

Benign

0.96

PhyloP100

1.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over