NM_002661.5:c.3125G>T

Variant names:

• chr16-81937830-G-T
• rs114262189
• NM_002661.5:c.3125G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002661.5(PLCG2):​c.3125G>T​(p.Ser1042Ile) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1042T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 8 publications found

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]

PLCG2 Gene-Disease associations (from GenCC):

• autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• familial cold autoinflammatory syndrome 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10171968).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002661.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.3125G>T	p.Ser1042Ile	missense	Exon 28 of 33	NP_002652.2
	PLCG2	NM_001425749.1		c.3125G>T	p.Ser1042Ile	missense	Exon 29 of 34	NP_001412678.1
	PLCG2	NM_001425750.1		c.3125G>T	p.Ser1042Ile	missense	Exon 28 of 33	NP_001412679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.3125G>T	p.Ser1042Ile	missense	Exon 28 of 33	ENSP00000482457.1
	PLCG2	ENST00000565054.7	TSL:5	c.3125G>T	p.Ser1042Ile	missense	Exon 29 of 34	ENSP00000520638.1
	PLCG2	ENST00000697580.2		c.3125G>T	p.Ser1042Ile	missense	Exon 28 of 33	ENSP00000520637.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.13	N
PhyloP100		2.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.039
Sift	Benign	0.48	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.51		Loss of disorder (P = 0.0036)
MVP		0.36
MPC		0.32
ClinPred		0.19	T
GERP RS		2.3
Varity_R		0.058
gMVP		0.50

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

Other links and lift over

dbSNP: rs114262189; hg19: chr16-81971435;