rs11548656

Variant names:

• chr16-81883307-A-G
• rs11548656
• NM_002661.5:c.731A>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.731A>G​(p.His244Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0313 in 1,613,968 control chromosomes in the GnomAD database, including 939 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (76 hom., cov: 32)
  • Exomes 𝑓: 0.032 (863 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.10
• Publications: 23 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=0.0069028437).
• BP6: Variant 16-81883307-A-G is Benign according to our data. Variant chr16-81883307-A-G is described in ClinVar as Benign. ClinVar VariationId is 472903.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 = 0.0263 (4002/152288) while in subpopulation NFE AF = 0.0377 (2564/68020). AF 95% confidence interval is 0.0365. There are 76 homozygotes in GnomAd4. There are 1960 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4002 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.731A>G	p.His244Arg	missense	Exon 9 of 33	NP_002652.2
	PLCG2	NM_001425749.1		c.731A>G	p.His244Arg	missense	Exon 10 of 34	NP_001412678.1
	PLCG2	NM_001425750.1		c.731A>G	p.His244Arg	missense	Exon 9 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.731A>G	p.His244Arg	missense	Exon 9 of 33	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.975A>G		non_coding_transcript_exon	Exon 8 of 20
	PLCG2	ENST00000565054.7	TSL:5	c.731A>G	p.His244Arg	missense	Exon 10 of 34	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4006 AN: 152170 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00792

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0253 AC: 6323 AN: 249542 AF XY: 0.0253

Gnomad AFR exome AF: 0.00678

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0328

GnomAD4 exome AF: 0.0318 AC: 46439 AN: 1461680 Hom.: 863 Cov.: 31 AF XY: 0.0312 AC XY: 22658 AN XY: 727158

African (AFR) AF: 0.00669 AC: 224 AN: 33478

American (AMR) AF: 0.0191 AC: 855 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 720 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00392 AC: 338 AN: 86256

European-Finnish (FIN) AF: 0.0473 AC: 2524 AN: 53378

Middle Eastern (MID) AF: 0.0241 AC: 139 AN: 5766

European-Non Finnish (NFE) AF: 0.0359 AC: 39901 AN: 1111850

Other (OTH) AF: 0.0288 AC: 1737 AN: 60396

GnomAD4 genome AF: 0.0263 AC: 4002 AN: 152288 Hom.: 76 Cov.: 32 AF XY: 0.0263 AC XY: 1960 AN XY: 74466

African (AFR) AF: 0.00789 AC: 328 AN: 41558

American (AMR) AF: 0.0210 AC: 321 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.0479 AC: 509 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2564 AN: 68020

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0306 Hom.: 52

Bravo AF: 0.0245

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0384 AC: 148

ESP6500AA AF: 0.00707 AC: 30

ESP6500EA AF: 0.0349 AC: 296

ExAC AF: 0.0253 AC: 3061

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0408

EpiControl AF: 0.0404

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Familial cold autoinflammatory syndrome 3 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.068
Sift	Benign	0.62	T
Sift4G	Benign	0.60	T
Polyphen		0.062	B
Vest4		0.34
MPC		0.16
ClinPred		0.025	T
GERP RS		5.1
PromoterAI		0.035	Neutral
Varity_R		0.17
gMVP		0.56
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11548656; hg19: chr16-81916912; COSMIC: COSV63868426;