rs150276286

chr16-81869274-C-Gchr16-81869274-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002661.5(PLCG2):c.540C>G(p.Ala180=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00906 in 1,613,054 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A180A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (79 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 16-81869274-C-G is Benign according to our data. Variant chr16-81869274-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 540126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81869274-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00637 (970/152286) while in subpopulation NFE AF= 0.0104 (705/68020). AF 95% confidence interval is 0.00973. There are 4 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 970 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.540C>G	p.Ala180=	synonymous_variant	6/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.540C>G	p.Ala180=	synonymous_variant	6/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 970 AN: 152168 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00604 AC: 1507 AN: 249528 Hom.: 7 AF XY: 0.00628 AC XY: 850 AN XY: 135378

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00480

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00949

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00935 AC: 13651 AN: 1460768 Hom.: 79 Cov.: 31 AF XY: 0.00926 AC XY: 6729 AN XY: 726776

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.00386

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00472

Gnomad4 FIN exome AF: 0.00189

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00843

GnomAD4 genome AF: 0.00637 AC: 970 AN: 152286 Hom.: 4 Cov.: 33 AF XY: 0.00584 AC XY: 435 AN XY: 74462

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00653 Hom.: 1

Bravo AF: 0.00647

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PLCG2: BP4, BP7, BS1, BS2 -

PLCG2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Familial cold autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	11
Dann	Benign	0.71

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: rs150276286; hg19: chr16-81902879; COSMIC: COSV63869564; COSMIC: COSV63869564;