16-81891389-C-G

Variant names:

• chr16-81891389-C-G
• rs4889428
• NM_002661.5:c.868-83C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002661.5(PLCG2):​c.868-83C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 818,470 control chromosomes in the GnomAD database, including 1 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 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000164 (25/152226) while in subpopulation EAS AF = 0.00368 (19/5170). AF 95% confidence interval is 0.00241. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 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.868-83C>G		intron	N/A	NP_002652.2
	PLCG2	NM_001425749.1		c.868-83C>G		intron	N/A	NP_001412678.1
	PLCG2	NM_001425750.1		c.868-83C>G		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>G		intron	N/A	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.1112-83C>G		intron	N/A
	PLCG2	ENST00000565054.7	TSL:5	c.868-83C>G		intron	N/A	ENSP00000520638.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000204 AC: 136 AN: 666244 Hom.: 1 AF XY: 0.000207 AC XY: 74 AN XY: 356980

African (AFR) AF: 0.00 AC: 0 AN: 18582

American (AMR) AF: 0.0000469 AC: 2 AN: 42628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19852

East Asian (EAS) AF: 0.00278 AC: 100 AN: 35996

South Asian (SAS) AF: 0.000163 AC: 11 AN: 67360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4168

European-Non Finnish (NFE) AF: 0.0000536 AC: 21 AN: 391796

Other (OTH) AF: 0.0000585 AC: 2 AN: 34172

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74408

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00368 AC: 19 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 579

Bravo AF: 0.000162

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.43
DANN	Benign	0.42
PhyloP100		-2.1

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: rs4889428; hg19: chr16-81924994;