Genetic Variant PLCG2:c.-47-62C>G (chr16-81785881-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002661.5(PLCG2):c.-47-62C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,010,280 control chromosomes in the GnomAD database, including 101,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 15688 hom., cov: 32)

Exomes 𝑓: 0.44 ( 85775 hom. )

Consequence

PLCG2
NM_002661.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.29

Variant links:

Genes affected

PLCG2 (HGNC:9066): (phospholipase C gamma 2) The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

PLCG2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-81785881-C-G is Benign according to our data. Variant chr16-81785881-C-G is described in ClinVar as [Benign]. Clinvar id is 1266240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.-47-62C>G	intron_variant	Intron 1 of 32	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.-47-62C>G	intron_variant	Intron 2 of 33		NP_001412678.1
PLCG2	NM_001425750.1 link	c.-47-62C>G	intron_variant	Intron 1 of 32		NP_001412679.1
PLCG2	NM_001425751.1 link	c.-47-62C>G	intron_variant	Intron 2 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.-47-62C>G		intron_variant	Intron 1 of 32	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.450

AC:

68360

AN:

151906

Hom.:

15676

Cov.:

show subpopulations

Gnomad AFR

AF:

0.517

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.384

Gnomad EAS

AF:

0.293

Gnomad SAS

AF:

0.639

Gnomad FIN

AF:

0.458

Gnomad MID

AF:

0.378

Gnomad NFE

AF:

0.427

Gnomad OTH

AF:

0.410

GnomAD4 exome

AF:

0.441

AC:

378352

AN:

858256

Hom.:

85775

Cov.:

AF XY:

0.447

AC XY:

195811

AN XY:

437872

show subpopulations

Gnomad4 AFR exome

AF:

0.517

Gnomad4 AMR exome

AF:

0.397

Gnomad4 ASJ exome

AF:

0.378

Gnomad4 EAS exome

AF:

0.337

Gnomad4 SAS exome

AF:

0.642

Gnomad4 FIN exome

AF:

0.460

Gnomad4 NFE exome

AF:

0.428

Gnomad4 OTH exome

AF:

0.433

GnomAD4 genome

AF:

0.450

AC:

68411

AN:

152024

Hom.:

15688

Cov.:

AF XY:

0.455

AC XY:

33820

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.517

Gnomad4 AMR

AF:

0.392

Gnomad4 ASJ

AF:

0.384

Gnomad4 EAS

AF:

0.293

Gnomad4 SAS

AF:

0.640

Gnomad4 FIN

AF:

0.458

Gnomad4 NFE

AF:

0.427

Gnomad4 OTH

AF:

0.411

Alfa

AF:

0.447

Hom.:

1896

Bravo

AF:

0.438

Asia WGS

AF:

0.442

AC:

1536

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.053

DANN

Benign

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over