rs187454354

chr16-81919590-G-A

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.2161G>A(p.Glu721Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,074 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (70 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.97

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=0.0067660213).
• BP6: Variant 16-81919590-G-A is Benign according to our data. Variant chr16-81919590-G-A is described in ClinVar as [Benign]. Clinvar id is 472896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00346 (527/152224) while in subpopulation AMR AF= 0.0309 (473/15286). AF 95% confidence interval is 0.0286. There are 17 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 526 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.2161G>A	p.Glu721Lys	missense_variant	20/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.2161G>A	p.Glu721Lys	missense_variant	20/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152106 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00781 AC: 1949 AN: 249556 Hom.: 63 AF XY: 0.00566 AC XY: 766 AN XY: 135402

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.0541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00511

GnomAD4 exome AF: 0.00177 AC: 2593 AN: 1461850 Hom.: 70 Cov.: 33 AF XY: 0.00147 AC XY: 1071 AN XY: 727230

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00660

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152224 Hom.: 17 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74428

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000441 Hom.: 2

Bravo AF: 0.00567

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00597 AC: 722

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Nov 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

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	0.18
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	0.90	D
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.13	T;T
Polyphen		0.0	B;.
Vest4		0.41
MVP		0.51
MPC		0.30
ClinPred		0.031	T
GERP RS		5.2
Varity_R		0.47
gMVP		0.62

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: rs187454354; hg19: chr16-81953195;