chr16-81910598-C-A

Variant names:

• chr16-81910598-C-A
• rs191668546
• NM_002661.5:c.1812C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002661.5(PLCG2):​c.1812C>A​(p.Asn604Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N604H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1812C>A	p.Asn604Lys	missense_variant	Exon 18 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.1812C>A	p.Asn604Lys	missense_variant	Exon 19 of 34		NP_001412678.1
PLCG2	NM_001425750.1	c.1812C>A	p.Asn604Lys	missense_variant	Exon 18 of 33		NP_001412679.1
PLCG2	NM_001425751.1	c.1812C>A	p.Asn604Lys	missense_variant	Exon 19 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1812C>A	p.Asn604Lys	missense_variant	Exon 18 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

⚠️ 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: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.70	N;.
PhyloP100		5.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	.;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.63		Gain of methylation at N604 (P = 0.0121);Gain of methylation at N604 (P = 0.0121);
MVP		0.90
MPC		0.85
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.80

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: rs191668546; hg19: chr16-81944203;