16-81910561-T-G

Variant names:

• chr16-81910561-T-G
• rs1555519696
• NM_002661.5:c.1775T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002661.5(PLCG2):​c.1775T>G​(p.Met592Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M592T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.839

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13996726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1775T>G	p.Met592Arg	missense_variant	Exon 18 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.1775T>G	p.Met592Arg	missense_variant	Exon 19 of 34		NP_001412678.1
PLCG2	NM_001425750.1	c.1775T>G	p.Met592Arg	missense_variant	Exon 18 of 33		NP_001412679.1
PLCG2	NM_001425751.1	c.1775T>G	p.Met592Arg	missense_variant	Exon 19 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1775T>G	p.Met592Arg	missense_variant	Exon 18 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 10, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.48	N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.090	.;N
REVEL	Benign	0.25
Sift	Benign	0.094	.;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0020	B;.
Vest4		0.44
MutPred		0.57		Gain of solvent accessibility (P = 0.0021);Gain of solvent accessibility (P = 0.0021);
MVP		0.57
MPC		0.42
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.28
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555519696; hg19: chr16-81944166;