16-81908423-C-G

Variant names:

• chr16-81908423-C-G
• rs72824905
• NM_002661.5:c.1565C>G

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.1565C>G​(p.Pro522Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,613,548 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P522S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (43 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.56
• Publications: 111 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=0.0038388371).
• BP6: Variant 16-81908423-C-G is Benign according to our data. Variant chr16-81908423-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00494 (752/152236) while in subpopulation NFE AF = 0.00882 (600/68006). AF 95% confidence interval is 0.00824. There are 3 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 752 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.1565C>G	p.Pro522Arg	missense	Exon 17 of 33	NP_002652.2
	PLCG2	NM_001425749.1		c.1565C>G	p.Pro522Arg	missense	Exon 18 of 34	NP_001412678.1
	PLCG2	NM_001425750.1		c.1565C>G	p.Pro522Arg	missense	Exon 17 of 33	NP_001412679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1565C>G	p.Pro522Arg	missense	Exon 17 of 33	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.1809C>G		non_coding_transcript_exon	Exon 16 of 20
	PLCG2	ENST00000565054.7	TSL:5	c.1565C>G	p.Pro522Arg	missense	Exon 18 of 34	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00882

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00518 AC: 1291 AN: 249084 AF XY: 0.00525

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00360

Gnomad ASJ exome AF: 0.00807

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00876

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00692 AC: 10118 AN: 1461312 Hom.: 43 Cov.: 31 AF XY: 0.00675 AC XY: 4909 AN XY: 726948

African (AFR) AF: 0.00105 AC: 35 AN: 33478

American (AMR) AF: 0.00401 AC: 179 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00831 AC: 217 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000604 AC: 52 AN: 86162

European-Finnish (FIN) AF: 0.00146 AC: 78 AN: 53396

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5762

European-Non Finnish (NFE) AF: 0.00826 AC: 9177 AN: 1111672

Other (OTH) AF: 0.00563 AC: 340 AN: 60370

GnomAD4 genome AF: 0.00494 AC: 752 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00439 AC XY: 327 AN XY: 74420

African (AFR) AF: 0.00128 AC: 53 AN: 41532

American (AMR) AF: 0.00255 AC: 39 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00882 AC: 600 AN: 68006

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00745 Hom.: 10

Bravo AF: 0.00526

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.000789 AC: 3

ESP6500EA AF: 0.00888 AC: 73

ExAC AF: 0.00504 AC: 609

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00993

EpiControl AF: 0.00943

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Familial cold autoinflammatory syndrome 3 (1)
-	-	1	PLCG2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		2.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.085
Sift	Benign	0.15	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.41
MPC		0.29
ClinPred		0.0084	T
GERP RS		4.8
Varity_R		0.050
gMVP		0.66
Mutation Taster		=92/8	polymorphism

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: rs72824905; hg19: chr16-81942028; COSMIC: COSV100842711; COSMIC: COSV100842711;