16-81854547-A-G

Variant names:

• chr16-81854547-A-G
• rs1143686
• NM_002661.5:c.297A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002661.5(PLCG2):​c.297A>G​(p.Leu99Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,612,678 control chromosomes in the GnomAD database, including 74,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L99L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5652 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69113 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.462
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-81854547-A-G is Benign according to our data. Variant chr16-81854547-A-G is described in ClinVar as Benign. ClinVar VariationId is 403317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.462 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 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.297A>G	p.Leu99Leu	synonymous	Exon 3 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.297A>G	p.Leu99Leu	synonymous	Exon 4 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.297A>G	p.Leu99Leu	synonymous	Exon 3 of 33	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.297A>G	p.Leu99Leu	synonymous	Exon 3 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.541A>G		non_coding_transcript_exon	Exon 2 of 20
	PLCG2	ENST00000902427.1		c.297A>G	p.Leu99Leu	synonymous	Exon 3 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39632 AN: 152000 Hom.: 5649 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.0851

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.277 AC: 69001 AN: 249418 AF XY: 0.281

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.0670

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.303 AC: 442480 AN: 1460560 Hom.: 69113 Cov.: 33 AF XY: 0.302 AC XY: 219647 AN XY: 726622

African (AFR) AF: 0.148 AC: 4950 AN: 33466

American (AMR) AF: 0.268 AC: 11998 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 8507 AN: 26124

East Asian (EAS) AF: 0.0891 AC: 3535 AN: 39696

South Asian (SAS) AF: 0.269 AC: 23236 AN: 86222

European-Finnish (FIN) AF: 0.322 AC: 17221 AN: 53406

Middle Eastern (MID) AF: 0.219 AC: 1264 AN: 5766

European-Non Finnish (NFE) AF: 0.319 AC: 354609 AN: 1110820

Other (OTH) AF: 0.284 AC: 17160 AN: 60342

GnomAD4 genome AF: 0.261 AC: 39632 AN: 152118 Hom.: 5652 Cov.: 32 AF XY: 0.260 AC XY: 19352 AN XY: 74354

African (AFR) AF: 0.157 AC: 6526 AN: 41506

American (AMR) AF: 0.274 AC: 4187 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3468

East Asian (EAS) AF: 0.0847 AC: 438 AN: 5170

South Asian (SAS) AF: 0.281 AC: 1355 AN: 4826

European-Finnish (FIN) AF: 0.321 AC: 3393 AN: 10566

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21645 AN: 67972

Other (OTH) AF: 0.276 AC: 585 AN: 2116

Alfa AF: 0.281 Hom.: 6316

Bravo AF: 0.249

Asia WGS AF: 0.174 AC: 606 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.320

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Familial cold autoinflammatory syndrome 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.48
DANN	Benign	0.38
PhyloP100		-0.46
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: rs1143686; hg19: chr16-81888152; COSMIC: COSV63870246; COSMIC: COSV63870246;