chr16-81910720-C-A

Variant names:

• chr16-81910720-C-A
• NM_002661.5:c.1934C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002661.5(PLCG2):​c.1934C>A​(p.Pro645Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLCG2 NM_002661.5 missense, splice_region
• Scores: Splicing: ADA: 0.01273
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1934C>A	p.Pro645Gln	missense_variant, splice_region_variant	Exon 18 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.1934C>A	p.Pro645Gln	missense_variant, splice_region_variant	Exon 19 of 34		NP_001412678.1
PLCG2	NM_001425750.1	c.1934C>A	p.Pro645Gln	missense_variant, splice_region_variant	Exon 18 of 33		NP_001412679.1
PLCG2	NM_001425751.1	c.1934C>A	p.Pro645Gln	missense_variant, splice_region_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.1934C>A	p.Pro645Gln	missense_variant, splice_region_variant	Exon 18 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454778 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.019
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.76	.;N
REVEL	Uncertain	0.32
Sift	Benign	0.066	.;T
Sift4G	Benign	0.14	T;T
Polyphen		0.083	B;.
Vest4		0.36
MutPred		0.32		Loss of catalytic residue at W646 (P = 0.0612);Loss of catalytic residue at W646 (P = 0.0612);
MVP		0.76
MPC		0.34
ClinPred		0.57	D
GERP RS		5.0
Varity_R		0.089
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.27
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81944325;