rs201080992

Variant names:

• chr16-81870866-C-A
• rs201080992
• NM_002661.5:c.579C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-81870866-C-A
• chr16-81870866-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002661.5(PLCG2):​c.579C>A​(p.His193Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,144 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. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H193D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.219
• Publications: 15 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13863498).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	NM_002661.5	MANE Select	c.579C>A	p.His193Gln	missense	Exon 7 of 33	NP_002652.2
	PLCG2	NM_001425749.1		c.579C>A	p.His193Gln	missense	Exon 8 of 34	NP_001412678.1
	PLCG2	NM_001425750.1		c.579C>A	p.His193Gln	missense	Exon 7 of 33	NP_001412679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.579C>A	p.His193Gln	missense	Exon 7 of 33	ENSP00000482457.1
	PLCG2	ENST00000567980.5	TSL:1	n.823C>A		non_coding_transcript_exon	Exon 6 of 20
	PLCG2	ENST00000902427.1		c.579C>A	p.His193Gln	missense	Exon 7 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442144 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 717626

African (AFR) AF: 0.00 AC: 0 AN: 32856

American (AMR) AF: 0.00 AC: 0 AN: 41972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39090

South Asian (SAS) AF: 0.00 AC: 0 AN: 83438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100592

Other (OTH) AF: 0.00 AC: 0 AN: 59594

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cold autoinflammatory syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.22
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.049
Sift	Benign	0.21	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.37
MPC		0.063
ClinPred		0.31	T
GERP RS		3.5
Varity_R		0.039
gMVP		0.31

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: rs201080992; hg19: chr16-81904471;