chr16-81871690-T-C

Variant names:

• chr16-81871690-T-C
• rs4997772
• NM_002661.5:c.648+755T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002661.5(PLCG2):​c.648+755T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 151,990 control chromosomes in the GnomAD database, including 23,497 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (23497 hom., cov: 32)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.542
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 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.648+755T>C		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.648+755T>C		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.648+755T>C		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.648+755T>C		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.892+755T>C		intron	N/A
	PLCG2	ENST00000565054.7	TSL:5	c.648+755T>C		intron	N/A	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83070 AN: 151870 Hom.: 23472 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.547 AC: 83145 AN: 151990 Hom.: 23497 Cov.: 32 AF XY: 0.551 AC XY: 40887 AN XY: 74260

African (AFR) AF: 0.393 AC: 16274 AN: 41422

American (AMR) AF: 0.570 AC: 8706 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2042 AN: 3472

East Asian (EAS) AF: 0.523 AC: 2711 AN: 5180

South Asian (SAS) AF: 0.609 AC: 2933 AN: 4814

European-Finnish (FIN) AF: 0.629 AC: 6637 AN: 10546

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41996 AN: 67980

Other (OTH) AF: 0.562 AC: 1184 AN: 2106

Alfa AF: 0.605 Hom.: 13104

Bravo AF: 0.537

Asia WGS AF: 0.602 AC: 2092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		-0.54
Mutation Taster		=100/0	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: rs4997772; hg19: chr16-81905295;