rs114618894

chr16-81928585-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002661.5(PLCG2):c.2542C>T(p.Leu848Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,609,336 control chromosomes in the GnomAD database, including 13 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. L848L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (5 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 2.55

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009259105).
• BP6: Variant 16-81928585-C-T is Benign according to our data. Variant chr16-81928585-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81928585-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00477 (727/152334) while in subpopulation AFR AF= 0.0165 (684/41566). AF 95% confidence interval is 0.0154. There are 8 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 724 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.2542C>T	p.Leu848Phe	missense_variant	24/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.2542C>T	p.Leu848Phe	missense_variant	24/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 724 AN: 152216 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00123 AC: 306 AN: 249564 Hom.: 2 AF XY: 0.000872 AC XY: 118 AN XY: 135396

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000585 AC: 853 AN: 1457002 Hom.: 5 Cov.: 28 AF XY: 0.000499 AC XY: 362 AN XY: 725242

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00477 AC: 727 AN: 152334 Hom.: 8 Cov.: 33 AF XY: 0.00438 AC XY: 326 AN XY: 74486

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000917 Hom.: 2

Bravo AF: 0.00530

ESP6500AA AF: 0.0146 AC: 56

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00132 AC: 159

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 24, 2020

- -

Familial cold autoinflammatory syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.96	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.16	T;T
Polyphen		0.99	D;.
Vest4		0.56
MVP		0.57
MPC		0.90
ClinPred		0.016	T
GERP RS		5.4
Varity_R		0.33
gMVP		0.76

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: rs114618894; hg19: chr16-81962190;