NM_002661.5:c.649-4535T>G

Variant names:

• chr16-81876375-T-G
• rs3935743
• NM_002661.5:c.649-4535T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002661.5(PLCG2):​c.649-4535T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 152,124 control chromosomes in the GnomAD database, including 56,684 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56684 hom., cov: 30)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.180
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

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.649-4535T>G		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.649-4535T>G		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.649-4535T>G		intron	N/A	NP_001412679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.649-4535T>G		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.893-4535T>G		intron	N/A
	PLCG2	ENST00000565054.7	TSL:5	c.649-4535T>G		intron	N/A	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130086 AN: 152006 Hom.: 56644 Cov.: 30

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.936

Gnomad AMR AF: 0.909

Gnomad ASJ AF: 0.873

Gnomad EAS AF: 0.977

Gnomad SAS AF: 0.918

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.868

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.856 AC: 130178 AN: 152124 Hom.: 56684 Cov.: 30 AF XY: 0.860 AC XY: 63955 AN XY: 74364

African (AFR) AF: 0.672 AC: 27865 AN: 41438

American (AMR) AF: 0.909 AC: 13900 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 3028 AN: 3470

East Asian (EAS) AF: 0.977 AC: 5048 AN: 5168

South Asian (SAS) AF: 0.918 AC: 4430 AN: 4826

European-Finnish (FIN) AF: 0.948 AC: 10046 AN: 10600

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.925 AC: 62915 AN: 68018

Other (OTH) AF: 0.869 AC: 1838 AN: 2114

Alfa AF: 0.897 Hom.: 199052

Bravo AF: 0.843

Asia WGS AF: 0.934 AC: 3249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.0
DANN	Benign	0.61
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs3935743; hg19: chr16-81909980;