rs16994453

Positions:

• chr20-8150296-C-A
• chr20-8150296-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000338037.11(PLCB1):​c.102C>A​(p.Asp34Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D34D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLCB1 ENST00000338037.11 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.640

Genes affected

PLCB1 (HGNC:15917): (phospholipase C beta 1) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCB1. . Gene score misZ 3.8345 (greater than the threshold 3.09). Trascript score misZ 3.6982 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 12, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, West syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20247781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.102C>A	p.Asp34Glu	missense_variant, splice_region_variant	2/32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.102C>A	p.Asp34Glu	missense_variant, splice_region_variant	2/33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.102C>A	p.Asp34Glu	missense_variant, splice_region_variant	2/32	1	NM_015192.4	ENSP00000338185	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1282140 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 646222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.63
DEOGEN2	Benign	0.19	.;T;.;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	.;D;T;T;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.78	N;N;.;.;N
MutationTaster	Benign	0.073	P;P;P
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.34	N;N;.;.;N
REVEL	Benign	0.16
Sift	Benign	0.83	T;T;.;.;T
Sift4G	Benign	0.81	T;T;T;T;T
Polyphen		0.28	B;B;.;.;B
Vest4		0.40
MutPred		0.36		Loss of ubiquitination at K30 (P = 0.0795);Loss of ubiquitination at K30 (P = 0.0795);Loss of ubiquitination at K30 (P = 0.0795);Loss of ubiquitination at K30 (P = 0.0795);Loss of ubiquitination at K30 (P = 0.0795);
MVP		0.55
MPC		0.15
ClinPred		0.14	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs16994453; hg19: chr20-8130943;