rs72824905

Variant names:

• chr16-81908423-C-A
• rs72824905
• NM_002661.5:c.1565C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-81908423-C-A
• chr16-81908423-C-G
• chr16-81908423-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002661.5(PLCG2):​c.1565C>A​(p.Pro522His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. P522R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14357322).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1565C>A	p.Pro522His	missense_variant	Exon 17 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.1565C>A	p.Pro522His	missense_variant	Exon 18 of 34		NP_001412678.1
PLCG2	NM_001425750.1	c.1565C>A	p.Pro522His	missense_variant	Exon 17 of 33		NP_001412679.1
PLCG2	NM_001425751.1	c.1565C>A	p.Pro522His	missense_variant	Exon 18 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1565C>A	p.Pro522His	missense_variant	Exon 17 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		2.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	.;N
REVEL	Benign	0.072
Sift	Benign	0.035	.;D
Sift4G	Benign	0.091	T;T
Polyphen		0.033	B;.
Vest4		0.098
MutPred		0.36		Loss of catalytic residue at P522 (P = 0.0715);Loss of catalytic residue at P522 (P = 0.0715);
MVP		0.52
MPC		0.39
ClinPred		0.25	T
GERP RS		4.8
Varity_R		0.059
gMVP		0.66
Mutation Taster		=94/6	polymorphism

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: rs72824905; hg19: chr16-81942028;