16-81889177-T-C

Position:

• chr16-81889177-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002661.5(PLCG2):​c.771T>C​(p.His257His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,587,818 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.98

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-81889177-T-C is Benign according to our data. Variant chr16-81889177-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 540125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81889177-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000901 (136/150874) while in subpopulation AMR AF= 0.00614 (92/14992). AF 95% confidence interval is 0.00512. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.771T>C	p.His257His	synonymous_variant	10/33	ENST00000564138.6	NP_002652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.771T>C	p.His257His	synonymous_variant	10/33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 136 AN: 150756 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00614

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00388

GnomAD3 exomes AF: 0.000650 AC: 154 AN: 236838 Hom.: 1 AF XY: 0.000609 AC XY: 78 AN XY: 128052

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000402

Gnomad OTH exome AF: 0.00171

GnomAD4 exome AF: 0.000348 AC: 500 AN: 1436944 Hom.: 3 Cov.: 27 AF XY: 0.000348 AC XY: 249 AN XY: 715166

Gnomad4 AFR exome AF: 0.0000905

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.0000567

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000901 AC: 136 AN: 150874 Hom.: 0 Cov.: 31 AF XY: 0.00102 AC XY: 75 AN XY: 73590

Gnomad4 AFR AF: 0.000170

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.00384

Alfa AF: 0.000621 Hom.: 0

Bravo AF: 0.00155

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PLCG2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

PLCG2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

This variant is classified as likely 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.072
DANN	Benign	0.64

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: rs369555285; hg19: chr16-81922782; COSMIC: COSV63875117; COSMIC: COSV63875117;