NM_002661.5:c.1558-18C>G

Variant names:

• chr16-81908398-C-G
• rs113312523
• NM_002661.5:c.1558-18C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002661.5(PLCG2):​c.1558-18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLCG2 NM_002661.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1558-18C>G		intron_variant	Intron 16 of 32	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.1558-18C>G		intron_variant	Intron 17 of 33		NP_001412678.1
PLCG2	NM_001425750.1	c.1558-18C>G		intron_variant	Intron 16 of 32		NP_001412679.1
PLCG2	NM_001425751.1	c.1558-18C>G		intron_variant	Intron 17 of 33		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1558-18C>G		intron_variant	Intron 16 of 32	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457680 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109374

Other (OTH) AF: 0.00 AC: 0 AN: 60238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.60
PhyloP100		-0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs113312523; hg19: chr16-81942003;