16-81928585-C-T

Variant names:

• chr16-81928585-C-T
• rs114618894
• NM_002661.5:c.2542C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002661.5(PLCG2):​c.2542C>T​(p.Leu848Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,609,336 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L848L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (5 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 2.55
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009259105).
• BP6: Variant 16-81928585-C-T is Benign according to our data. Variant chr16-81928585-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00477 (727/152334) while in subpopulation AFR AF = 0.0165 (684/41566). AF 95% confidence interval is 0.0154. There are 8 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 727 AD gene.

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.2542C>T	p.Leu848Phe	missense	Exon 24 of 33	NP_002652.2
	PLCG2	NM_001425749.1		c.2542C>T	p.Leu848Phe	missense	Exon 25 of 34	NP_001412678.1
	PLCG2	NM_001425750.1		c.2542C>T	p.Leu848Phe	missense	Exon 24 of 33	NP_001412679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.2542C>T	p.Leu848Phe	missense	Exon 24 of 33	ENSP00000482457.1
	PLCG2	ENST00000902427.1		c.2695C>T	p.Leu899Phe	missense	Exon 25 of 34	ENSP00000572486.1
	PLCG2	ENST00000565054.7	TSL:5	c.2542C>T	p.Leu848Phe	missense	Exon 25 of 34	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 724 AN: 152216 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00123 AC: 306 AN: 249564 AF XY: 0.000872

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000585 AC: 853 AN: 1457002 Hom.: 5 Cov.: 28 AF XY: 0.000499 AC XY: 362 AN XY: 725242

African (AFR) AF: 0.0193 AC: 645 AN: 33358

American (AMR) AF: 0.00136 AC: 61 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5754

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1107584

Other (OTH) AF: 0.00181 AC: 109 AN: 60244

GnomAD4 genome AF: 0.00477 AC: 727 AN: 152334 Hom.: 8 Cov.: 33 AF XY: 0.00438 AC XY: 326 AN XY: 74486

African (AFR) AF: 0.0165 AC: 684 AN: 41566

American (AMR) AF: 0.00189 AC: 29 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00159 Hom.: 5

Bravo AF: 0.00530

ESP6500AA AF: 0.0146 AC: 56

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00132 AC: 159

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
1	-	-	Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (1)
-	-	1	Familial cold autoinflammatory syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.96	L
PhyloP100		2.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Benign	0.094	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.56
MVP		0.57
MPC		0.90
ClinPred		0.016	T
GERP RS		5.4
Varity_R		0.33
gMVP		0.76
Mutation Taster		=86/14	polymorphism

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: rs114618894; hg19: chr16-81962190;