rs12448089

Variant names:

• chr16-81929022-G-A
• rs12448089
• NM_002661.5:c.2581+398G>A

Variant summary

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

The NM_002661.5(PLCG2):​c.2581+398G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 152,000 control chromosomes in the GnomAD database, including 36,309 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 0.68 (36309 hom., cov: 34)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.31
• Publications: 1 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 (EAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.2581+398G>A		intron_variant	Intron 24 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.2581+398G>A		intron_variant	Intron 25 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.2581+398G>A		intron_variant	Intron 24 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.2581+398G>A		intron_variant	Intron 25 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.2581+398G>A		intron_variant	Intron 24 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104008 AN: 151882 Hom.: 36306 Cov.: 34

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.704

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

GnomAD4 genome AF: 0.684 AC: 104041 AN: 152000 Hom.: 36309 Cov.: 34 AF XY: 0.689 AC XY: 51178 AN XY: 74302

African (AFR) AF: 0.534 AC: 22164 AN: 41468

American (AMR) AF: 0.776 AC: 11867 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2451 AN: 3466

East Asian (EAS) AF: 0.809 AC: 4180 AN: 5166

South Asian (SAS) AF: 0.723 AC: 3486 AN: 4820

European-Finnish (FIN) AF: 0.731 AC: 7716 AN: 10556

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49846 AN: 67922

Other (OTH) AF: 0.705 AC: 1488 AN: 2112

Alfa AF: 0.702 Hom.: 4715

Bravo AF: 0.686

Asia WGS AF: 0.762 AC: 2649 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	0.0050
DANN	Benign	0.33
PhyloP100		-3.3
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: rs12448089; hg19: chr16-81962627;