15-40288759-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004573.3(PLCB2):c.3514G>A(p.Asp1172Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLCB2 NM_004573.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.390

Genes affected

PLCB2 (HGNC:9055): (phospholipase C beta 2) The protein encoded by this gene is a phosphodiesterase that catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. The encoded protein is activated by G proteins and has been shown to be involved in the type 2 taste receptor signal transduction pathway. In addition, nuclear factor kappa B can regulate the transcription of this gene, whose protein product is also an important regulator of platelet responses. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081216365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB2	NM_004573.3	c.3514G>A	p.Asp1172Asn	missense_variant	32/32	ENST00000260402.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB2	ENST00000260402.8	c.3514G>A	p.Asp1172Asn	missense_variant	32/32	2	NM_004573.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000811 AC: 2 AN: 246550 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459640 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.3514G>A (p.D1172N) alteration is located in exon 32 (coding exon 32) of the PLCB2 gene. This alteration results from a G to A substitution at nucleotide position 3514, causing the aspartic acid (D) at amino acid position 1172 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.086
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.36	B;P;.
Vest4		0.059
MutPred		0.15		Loss of methylation at K1177 (P = 0.2381);.;.;
MVP		0.57
MPC		0.36
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.065
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs748566293; hg19: chr15-40580960;