rs1071644

Variant names:

• chr16-81937798-T-C
• rs1071644
• NM_002661.5:c.3093T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002661.5(PLCG2):​c.3093T>C​(p.Asn1031Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,613,270 control chromosomes in the GnomAD database, including 200,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (14051 hom., cov: 32)
  • Exomes 𝑓: 0.50 (186935 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.489

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-81937798-T-C is Benign according to our data. Variant chr16-81937798-T-C is described in ClinVar as [Benign]. Clinvar id is 403324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81937798-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.3093T>C	p.Asn1031Asn	synonymous_variant	Exon 28 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.3093T>C	p.Asn1031Asn	synonymous_variant	Exon 29 of 34		NP_001412678.1
PLCG2	NM_001425750.1	c.3093T>C	p.Asn1031Asn	synonymous_variant	Exon 28 of 33		NP_001412679.1
PLCG2	NM_001425751.1	c.3093T>C	p.Asn1031Asn	synonymous_variant	Exon 29 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.3093T>C	p.Asn1031Asn	synonymous_variant	Exon 28 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59920 AN: 151988 Hom.: 14054 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.445 AC: 110907 AN: 249252 Hom.: 26747 AF XY: 0.458 AC XY: 61990 AN XY: 135216

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.433

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.528

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.499 AC: 728819 AN: 1461164 Hom.: 186935 Cov.: 36 AF XY: 0.499 AC XY: 363069 AN XY: 726914

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.289

Gnomad4 ASJ exome AF: 0.564

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.526

Gnomad4 OTH exome AF: 0.475

GnomAD4 genome AF: 0.394 AC: 59912 AN: 152106 Hom.: 14051 Cov.: 32 AF XY: 0.392 AC XY: 29119 AN XY: 74346

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.410

Alfa AF: 0.462 Hom.: 13985

Bravo AF: 0.372

Asia WGS AF: 0.327 AC: 1136 AN: 3478

EpiCase AF: 0.528

EpiControl AF: 0.530

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 12, 2023

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 58% of patients studied by a panel of primary immunodeficiencies. Number of patients: 56. Only high quality variants are reported. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Familial cold autoinflammatory syndrome 3 Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Benign:1

Oct 25, 2021

Genome-Nilou Lab

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	-0.52
CADD	Benign	1.1
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1071644; hg19: chr16-81971403; COSMIC: COSV63872588; COSMIC: COSV63872588;