16-81780739-T-C

Variant names:

• chr16-81780739-T-C
• rs4398100
• NM_002661.5:c.-48+1315T>C

Variant summary

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

The NM_002661.5(PLCG2):​c.-48+1315T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 152,202 control chromosomes in the GnomAD database, including 54,524 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 0.85 (54524 hom., cov: 32)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.96
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.-48+1315T>C		intron_variant	Intron 1 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.-47-5204T>C		intron_variant	Intron 2 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.-47-5204T>C		intron_variant	Intron 1 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.-47-5204T>C		intron_variant	Intron 2 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.-48+1315T>C		intron_variant	Intron 1 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128636 AN: 152084 Hom.: 54478 Cov.: 32

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.869

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.903

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.833

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

GnomAD4 genome AF: 0.846 AC: 128739 AN: 152202 Hom.: 54524 Cov.: 32 AF XY: 0.850 AC XY: 63254 AN XY: 74426

African (AFR) AF: 0.857 AC: 35583 AN: 41516

American (AMR) AF: 0.870 AC: 13306 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2748 AN: 3470

East Asian (EAS) AF: 0.903 AC: 4680 AN: 5184

South Asian (SAS) AF: 0.951 AC: 4591 AN: 4830

European-Finnish (FIN) AF: 0.845 AC: 8942 AN: 10588

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56204 AN: 68000

Other (OTH) AF: 0.835 AC: 1761 AN: 2110

Alfa AF: 0.839 Hom.: 25582

Bravo AF: 0.842

Asia WGS AF: 0.926 AC: 3219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.35
PhyloP100		-5.0
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: rs4398100; hg19: chr16-81814344;