rs1143690

chr16-81936242-C-T

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.2916C>T(p.Val972=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,614,092 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (220 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (242 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82

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=-0.75).
• BP6: Variant 16-81936242-C-T is Benign according to our data. Variant chr16-81936242-C-T is described in ClinVar as [Benign]. Clinvar id is 472899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81936242-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.2916C>T	p.Val972=	synonymous_variant	27/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.2916C>T	p.Val972=	synonymous_variant	27/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.0318 AC: 4844 AN: 152096 Hom.: 219 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00856 AC: 2135 AN: 249470 Hom.: 93 AF XY: 0.00651 AC XY: 881 AN XY: 135346

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00353 AC: 5161 AN: 1461878 Hom.: 242 Cov.: 33 AF XY: 0.00308 AC XY: 2242 AN XY: 727240

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00651

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.00735

GnomAD4 genome AF: 0.0319 AC: 4852 AN: 152214 Hom.: 220 Cov.: 32 AF XY: 0.0300 AC XY: 2233 AN XY: 74434

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0133 Hom.: 70

Bravo AF: 0.0357

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Familial cold autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.10
Dann	Benign	0.63

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: rs1143690; hg19: chr16-81969847; COSMIC: COSV63870054; COSMIC: COSV63870054;