16-81891389-C-T

Variant names:

• chr16-81891389-C-T
• rs4889428
• NM_002661.5:c.868-83C>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.868-83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 818,028 control chromosomes in the GnomAD database, including 5,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (709 hom., cov: 33)
  • Exomes 𝑓: 0.11 (4566 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.12
• Publications: 5 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 (BayesDel_noAF=-0.82).
• BP6: Variant 16-81891389-C-T is Benign according to our data. Variant chr16-81891389-C-T is described in ClinVar as Benign. ClinVar VariationId is 1273765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.146 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.868-83C>T		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.868-83C>T		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.868-83C>T		intron	N/A	NP_001412679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.868-83C>T		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.1112-83C>T		intron	N/A
	PLCG2	ENST00000565054.7	TSL:5	c.868-83C>T		intron	N/A	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.0850 AC: 12923 AN: 152082 Hom.: 709 Cov.: 33

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0687

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0278

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0851

GnomAD4 exome AF: 0.110 AC: 73226 AN: 665828 Hom.: 4566 AF XY: 0.114 AC XY: 40834 AN XY: 356752

African (AFR) AF: 0.0195 AC: 362 AN: 18582

American (AMR) AF: 0.0525 AC: 2237 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3010 AN: 19838

East Asian (EAS) AF: 0.0246 AC: 884 AN: 35996

South Asian (SAS) AF: 0.156 AC: 10522 AN: 67314

European-Finnish (FIN) AF: 0.127 AC: 6557 AN: 51652

Middle Eastern (MID) AF: 0.105 AC: 436 AN: 4166

European-Non Finnish (NFE) AF: 0.116 AC: 45501 AN: 391506

Other (OTH) AF: 0.109 AC: 3717 AN: 34158

GnomAD4 genome AF: 0.0849 AC: 12918 AN: 152200 Hom.: 709 Cov.: 33 AF XY: 0.0859 AC XY: 6387 AN XY: 74390

African (AFR) AF: 0.0188 AC: 780 AN: 41550

American (AMR) AF: 0.0686 AC: 1050 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 519 AN: 3470

East Asian (EAS) AF: 0.0277 AC: 143 AN: 5168

South Asian (SAS) AF: 0.155 AC: 745 AN: 4814

European-Finnish (FIN) AF: 0.127 AC: 1348 AN: 10582

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8059 AN: 68000

Other (OTH) AF: 0.0842 AC: 178 AN: 2114

Alfa AF: 0.0998 Hom.: 579

Bravo AF: 0.0770

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.69
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4889428; hg19: chr16-81924994; COSMIC: COSV63872574; COSMIC: COSV63872574;