16-81878673-C-T

Variant names:

• chr16-81878673-C-T
• rs11644436
• NM_002661.5:c.649-2237C>T

Variant summary

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

The NM_002661.5(PLCG2):​c.649-2237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,088 control chromosomes in the GnomAD database, including 2,642 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 0.18 (2642 hom., cov: 30)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.548
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.649-2237C>T		intron_variant	Intron 7 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.649-2237C>T		intron_variant	Intron 8 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.649-2237C>T		intron_variant	Intron 7 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.649-2237C>T		intron_variant	Intron 8 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.649-2237C>T		intron_variant	Intron 7 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27318 AN: 151968 Hom.: 2639 Cov.: 30

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0206

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.222

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.180 AC: 27337 AN: 152088 Hom.: 2642 Cov.: 30 AF XY: 0.174 AC XY: 12964 AN XY: 74342

African (AFR) AF: 0.154 AC: 6368 AN: 41474

American (AMR) AF: 0.145 AC: 2218 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 723 AN: 3468

East Asian (EAS) AF: 0.0207 AC: 107 AN: 5178

South Asian (SAS) AF: 0.176 AC: 850 AN: 4820

European-Finnish (FIN) AF: 0.129 AC: 1368 AN: 10594

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15104 AN: 67970

Other (OTH) AF: 0.187 AC: 395 AN: 2112

Alfa AF: 0.187 Hom.: 1565

Bravo AF: 0.179

Asia WGS AF: 0.0970 AC: 338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.44
PhyloP100		0.55
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: rs11644436; hg19: chr16-81912278;