16-81786000-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002661.5(PLCG2):c.11C>T(p.Thr4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. T4T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (1 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.323

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008903146).
• BP6: Variant 16-81786000-C-T is Benign according to our data. Variant chr16-81786000-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 732127.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000335 (51/152304) while in subpopulation AFR AF= 0.000866 (36/41556). AF 95% confidence interval is 0.000643. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.11C>T	p.Thr4Met	missense_variant	2/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.11C>T	p.Thr4Met	missense_variant	2/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000233 AC: 58 AN: 248706 Hom.: 1 AF XY: 0.000245 AC XY: 33 AN XY: 134886

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000979 AC: 143 AN: 1461240 Hom.: 1 Cov.: 30 AF XY: 0.0000977 AC XY: 71 AN XY: 726882

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74480

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000952 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.00103 AC: 4

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	11
Dann	Benign	0.91
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.28	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.13	N;.;N
Sift	Benign	0.21	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.10, 0.10
MVP		0.53
MPC		0.065
ClinPred		0.0048	T
GERP RS		-0.32
Varity_R		0.011
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs199972098; hg19: chr16-81819605; COSMIC: COSV63877389;