rs8045964

Variant names:

• chr16-81783128-C-T
• rs8045964
• NM_002661.5:c.-47-2815C>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.-47-2815C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 489,572 control chromosomes in the GnomAD database, including 50,431 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 0.42 (13640 hom., cov: 30)
  • Exomes 𝑓: 0.46 (36791 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.440
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• familial cold autoinflammatory syndrome 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

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 (SAS) allele frequency at 95% confidence interval = 0.615 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.-47-2815C>T		intron	N/A	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.-47-2815C>T		intron	N/A	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.-47-2815C>T		intron	N/A	NP_001412679.1	P16885

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.-47-2815C>T		intron	N/A	ENSP00000482457.1	P16885
	PLCG2	ENST00000902427.1		c.-47-2815C>T		intron	N/A	ENSP00000572486.1
	PLCG2	ENST00000565054.7	TSL:5	c.-47-2815C>T		intron	N/A	ENSP00000520638.1	P16885

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63791 AN: 151652 Hom.: 13632 Cov.: 30

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.397

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.389

GnomAD2 exomes AF: 0.428 AC: 78888 AN: 184232 AF XY: 0.442

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.456 AC: 154110 AN: 337802 Hom.: 36791 Cov.: 0 AF XY: 0.472 AC XY: 91091 AN XY: 192886

African (AFR) AF: 0.405 AC: 4075 AN: 10054

American (AMR) AF: 0.366 AC: 11588 AN: 31650

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 4295 AN: 11188

East Asian (EAS) AF: 0.290 AC: 3560 AN: 12264

South Asian (SAS) AF: 0.633 AC: 39351 AN: 62140

European-Finnish (FIN) AF: 0.463 AC: 7012 AN: 15138

Middle Eastern (MID) AF: 0.383 AC: 1032 AN: 2696

European-Non Finnish (NFE) AF: 0.433 AC: 76617 AN: 177116

Other (OTH) AF: 0.423 AC: 6580 AN: 15556

GnomAD4 genome AF: 0.421 AC: 63833 AN: 151770 Hom.: 13640 Cov.: 30 AF XY: 0.425 AC XY: 31545 AN XY: 74150

African (AFR) AF: 0.412 AC: 17031 AN: 41376

American (AMR) AF: 0.366 AC: 5576 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 1375 AN: 3464

East Asian (EAS) AF: 0.284 AC: 1460 AN: 5148

South Asian (SAS) AF: 0.634 AC: 3048 AN: 4808

European-Finnish (FIN) AF: 0.460 AC: 4830 AN: 10510

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29362 AN: 67910

Other (OTH) AF: 0.390 AC: 823 AN: 2108

Alfa AF: 0.419 Hom.: 4086

Bravo AF: 0.404

Asia WGS AF: 0.429 AC: 1491 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	1.5
DANN	Benign	0.55
PhyloP100		-0.44
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: rs8045964; hg19: chr16-81816733; COSMIC: COSV63869127; COSMIC: COSV63869127;