rs13333716

Variant names:

• chr16-81895922-C-G
• rs13333716
• NM_002661.5:c.1188C>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.1188C>G​(p.Thr396Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0696 in 1,613,924 control chromosomes in the GnomAD database, including 4,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (375 hom., cov: 31)
  • Exomes 𝑓: 0.070 (4020 hom.)
• Consequence: PLCG2 NM_002661.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.194
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-81895922-C-G is Benign according to our data. Variant chr16-81895922-C-G is described in ClinVar as Benign. ClinVar VariationId is 403321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.194 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 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.1188C>G	p.Thr396Thr	synonymous	Exon 13 of 33	NP_002652.2	P16885
	PLCG2	NM_001425749.1		c.1188C>G	p.Thr396Thr	synonymous	Exon 14 of 34	NP_001412678.1	P16885
	PLCG2	NM_001425750.1		c.1188C>G	p.Thr396Thr	synonymous	Exon 13 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.1188C>G	p.Thr396Thr	synonymous	Exon 13 of 33	ENSP00000482457.1	P16885
	PLCG2	ENST00000567980.5	TSL:1	n.1432C>G		non_coding_transcript_exon	Exon 12 of 20
	PLCG2	ENST00000902427.1		c.1188C>G	p.Thr396Thr	synonymous	Exon 13 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9901 AN: 152010 Hom.: 372 Cov.: 31

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0484

GnomAD2 exomes AF: 0.0525 AC: 13089 AN: 249510 AF XY: 0.0518

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0394

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.0517

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0540

GnomAD4 exome AF: 0.0700 AC: 102330 AN: 1461796 Hom.: 4020 Cov.: 33 AF XY: 0.0684 AC XY: 49743 AN XY: 727202

African (AFR) AF: 0.0824 AC: 2758 AN: 33478

American (AMR) AF: 0.0364 AC: 1628 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 1017 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0274 AC: 2364 AN: 86254

European-Finnish (FIN) AF: 0.0514 AC: 2746 AN: 53406

Middle Eastern (MID) AF: 0.0378 AC: 218 AN: 5768

European-Non Finnish (NFE) AF: 0.0788 AC: 87601 AN: 1111938

Other (OTH) AF: 0.0661 AC: 3993 AN: 60392

GnomAD4 genome AF: 0.0652 AC: 9920 AN: 152128 Hom.: 375 Cov.: 31 AF XY: 0.0629 AC XY: 4674 AN XY: 74364

African (AFR) AF: 0.0812 AC: 3367 AN: 41470

American (AMR) AF: 0.0442 AC: 675 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0256 AC: 123 AN: 4808

European-Finnish (FIN) AF: 0.0479 AC: 508 AN: 10600

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0724 AC: 4923 AN: 68012

Other (OTH) AF: 0.0479 AC: 101 AN: 2110

Alfa AF: 0.0673 Hom.: 134

Bravo AF: 0.0661

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0715

EpiControl AF: 0.0722

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.5
DANN	Benign	0.54
PhyloP100		-0.19
Mutation Taster		=73/27	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: rs13333716; hg19: chr16-81929527;