16-81950832-A-G

Variant names:

• chr16-81950832-A-G
• rs4888197
• NM_002661.5:c.3570+4569A>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.3570+4569A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,250 control chromosomes in the GnomAD database, including 1,411 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 0.13 (1411 hom., cov: 33)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.202
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.182 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.3570+4569A>G		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.3570+4569A>G		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.3570+4569A>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.3570+4569A>G		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000565054.7	TSL:5	c.3570+4569A>G		intron	N/A	ENSP00000520638.1
	PLCG2	ENST00000697580.2		c.3570+4569A>G		intron	N/A	ENSP00000520637.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20227 AN: 152132 Hom.: 1404 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0700

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.146

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

GnomAD4 genome AF: 0.133 AC: 20268 AN: 152250 Hom.: 1411 Cov.: 33 AF XY: 0.130 AC XY: 9703 AN XY: 74442

African (AFR) AF: 0.113 AC: 4712 AN: 41540

American (AMR) AF: 0.188 AC: 2875 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3470

East Asian (EAS) AF: 0.187 AC: 970 AN: 5184

South Asian (SAS) AF: 0.0702 AC: 339 AN: 4828

European-Finnish (FIN) AF: 0.0979 AC: 1039 AN: 10608

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9458 AN: 68004

Other (OTH) AF: 0.153 AC: 323 AN: 2114

Alfa AF: 0.137 Hom.: 4067

Bravo AF: 0.142

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.8
DANN	Benign	0.78
PhyloP100		0.20
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: rs4888197; hg19: chr16-81984437;