rs12716928

Variant names:

• chr16-81945447-A-G
• rs12716928
• NM_002661.5:c.3482-728A>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.3482-728A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 152,310 control chromosomes in the GnomAD database, including 62,415 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 0.90 (62415 hom., cov: 34)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.592
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.3482-728A>G		intron_variant	Intron 30 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.3482-728A>G		intron_variant	Intron 31 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.3482-728A>G		intron_variant	Intron 30 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.3482-728A>G		intron_variant	Intron 31 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.3482-728A>G		intron_variant	Intron 30 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.904 AC: 137600 AN: 152192 Hom.: 62361 Cov.: 34

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.941

Gnomad FIN AF: 0.925

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.909

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

GnomAD4 genome AF: 0.904 AC: 137715 AN: 152310 Hom.: 62415 Cov.: 34 AF XY: 0.905 AC XY: 67421 AN XY: 74470

African (AFR) AF: 0.825 AC: 34280 AN: 41548

American (AMR) AF: 0.944 AC: 14447 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 3262 AN: 3472

East Asian (EAS) AF: 0.957 AC: 4960 AN: 5184

South Asian (SAS) AF: 0.941 AC: 4549 AN: 4832

European-Finnish (FIN) AF: 0.925 AC: 9822 AN: 10616

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63317 AN: 68028

Other (OTH) AF: 0.911 AC: 1927 AN: 2116

Alfa AF: 0.925 Hom.: 38325

Bravo AF: 0.902

Asia WGS AF: 0.947 AC: 3290 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.33
DANN	Benign	0.58
PhyloP100		-0.59
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: rs12716928; hg19: chr16-81979052;