16-81889208-C-T

Variant names:

• chr16-81889208-C-T
• rs1143687
• NM_002661.5:c.802C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002661.5(PLCG2):​c.802C>T​(p.Arg268Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,602,822 control chromosomes in the GnomAD database, including 3,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (210 hom., cov: 31)
  • Exomes 𝑓: 0.058 (2872 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.789
• Publications: 25 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• familial cold autoinflammatory syndrome 3

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027187467).
• BP6: Variant 16-81889208-C-T is Benign according to our data. Variant chr16-81889208-C-T is described in ClinVar as Benign. ClinVar VariationId is 403319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0666 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.802C>T	p.Arg268Trp	missense	Exon 10 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.802C>T	p.Arg268Trp	missense	Exon 11 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.802C>T	p.Arg268Trp	missense	Exon 10 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.802C>T	p.Arg268Trp	missense	Exon 10 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.1046C>T		non_coding_transcript_exon	Exon 9 of 20
	PLCG2	ENST00000902427.1		c.802C>T	p.Arg268Trp	missense	Exon 10 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6836 AN: 149408 Hom.: 210 Cov.: 31

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0444

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0171

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.0515

GnomAD2 exomes AF: 0.0465 AC: 11244 AN: 242006 AF XY: 0.0470

Gnomad AFR exome AF: 0.00950

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0502

Gnomad NFE exome AF: 0.0652

Gnomad OTH exome AF: 0.0544

GnomAD4 exome AF: 0.0581 AC: 84487 AN: 1453296 Hom.: 2872 Cov.: 29 AF XY: 0.0576 AC XY: 41625 AN XY: 722636

African (AFR) AF: 0.0101 AC: 337 AN: 33400

American (AMR) AF: 0.0351 AC: 1554 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2704 AN: 25906

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39658

South Asian (SAS) AF: 0.0159 AC: 1350 AN: 84918

European-Finnish (FIN) AF: 0.0511 AC: 2719 AN: 53166

Middle Eastern (MID) AF: 0.0545 AC: 313 AN: 5748

European-Non Finnish (NFE) AF: 0.0652 AC: 72101 AN: 1106136

Other (OTH) AF: 0.0566 AC: 3404 AN: 60124

GnomAD4 genome AF: 0.0457 AC: 6834 AN: 149526 Hom.: 210 Cov.: 31 AF XY: 0.0441 AC XY: 3210 AN XY: 72788

African (AFR) AF: 0.0111 AC: 451 AN: 40672

American (AMR) AF: 0.0444 AC: 655 AN: 14762

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 357 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.0172 AC: 76 AN: 4428

European-Finnish (FIN) AF: 0.0487 AC: 499 AN: 10242

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0682 AC: 4614 AN: 67614

Other (OTH) AF: 0.0510 AC: 105 AN: 2060

Alfa AF: 0.0616 Hom.: 1406

Bravo AF: 0.0454

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.0115 AC: 46

ESP6500EA AF: 0.0694 AC: 580

ExAC AF: 0.0445 AC: 5386

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Familial cold autoinflammatory syndrome 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.79
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.98	N
REVEL	Benign	0.15
Sift	Benign	0.030	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.39
MPC		0.34
ClinPred		0.025	T
GERP RS		2.8
Varity_R		0.15
gMVP		0.72
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1143687; hg19: chr16-81922813; COSMIC: COSV63873174; COSMIC: COSV63873174;