17-66688960-G-A

Variant names:

• chr17-66688960-G-A
• rs2227857
• NM_002737.3:c.831G>A

Variant summary

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

The NM_002737.3(PRKCA):​c.831G>A​(p.Leu277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,590,964 control chromosomes in the GnomAD database, including 95,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6907 hom., cov: 32)
  • Exomes 𝑓: 0.35 (89069 hom.)
• Consequence: PRKCA NM_002737.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.69
• Publications: 26 publications found

Genes affected

PRKCA (HGNC:9393): (protein kinase C alpha) Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the 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 family members 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 a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been reported to play roles in many different cellular processes, such as cell adhesion, cell transformation, cell cycle checkpoint, and cell volume control. Knockout studies in mice suggest that this kinase may be a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-66688960-G-A is Benign according to our data. Variant chr17-66688960-G-A is described in ClinVar as [Benign]. Clinvar id is 1295165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKCA	NM_002737.3	c.831G>A	p.Leu277Leu	synonymous_variant	Exon 8 of 17	ENST00000413366.8	NP_002728.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKCA	ENST00000413366.8	c.831G>A	p.Leu277Leu	synonymous_variant	Exon 8 of 17	1	NM_002737.3	ENSP00000408695.3
PRKCA	ENST00000578063.5	n.831G>A		non_coding_transcript_exon_variant	Exon 8 of 10	1		ENSP00000462087.1
PRKCA	ENST00000284384.6	n.*433G>A		non_coding_transcript_exon_variant	Exon 9 of 15	5		ENSP00000284384.6
PRKCA	ENST00000284384.6	n.*433G>A		3_prime_UTR_variant	Exon 9 of 15	5		ENSP00000284384.6

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42653 AN: 151822 Hom.: 6904 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.316 AC: 77590 AN: 245280 AF XY: 0.325

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.420

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.345 AC: 497127 AN: 1439026 Hom.: 89069 Cov.: 29 AF XY: 0.346 AC XY: 248210 AN XY: 716542

African (AFR) AF: 0.107 AC: 3530 AN: 33080

American (AMR) AF: 0.300 AC: 13075 AN: 43590

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 10881 AN: 25914

East Asian (EAS) AF: 0.131 AC: 5157 AN: 39512

South Asian (SAS) AF: 0.354 AC: 29819 AN: 84250

European-Finnish (FIN) AF: 0.367 AC: 19559 AN: 53272

Middle Eastern (MID) AF: 0.374 AC: 2139 AN: 5718

European-Non Finnish (NFE) AF: 0.359 AC: 393009 AN: 1094072

Other (OTH) AF: 0.335 AC: 19958 AN: 59618

GnomAD4 genome AF: 0.281 AC: 42661 AN: 151938 Hom.: 6907 Cov.: 32 AF XY: 0.283 AC XY: 21003 AN XY: 74230

African (AFR) AF: 0.119 AC: 4947 AN: 41458

American (AMR) AF: 0.299 AC: 4569 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1442 AN: 3470

East Asian (EAS) AF: 0.111 AC: 574 AN: 5168

South Asian (SAS) AF: 0.340 AC: 1631 AN: 4794

European-Finnish (FIN) AF: 0.382 AC: 4015 AN: 10510

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24355 AN: 67962

Other (OTH) AF: 0.296 AC: 624 AN: 2108

Alfa AF: 0.320 Hom.: 15830

Bravo AF: 0.266

Asia WGS AF: 0.240 AC: 836 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 17, 2021

GeneDx

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	-0.42
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2227857; hg19: chr17-64685078; COSMIC: COSV52591389;