rs775341189

Variant names:

• chr20-8760458-C-A
• rs775341189
• NM_015192.4:c.2708C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-8760458-C-A
• chr20-8760458-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015192.4(PLCB1):​c.2708C>A​(p.Thr903Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLCB1 NM_015192.4 missense, splice_region
• Scores: Splicing: ADA: 0.9252
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45
• Publications: 0 publications found

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]

PLCB1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 12

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3698639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.2708C>A	p.Thr903Lys	missense_variant, splice_region_variant	Exon 25 of 32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.2708C>A	p.Thr903Lys	missense_variant, splice_region_variant	Exon 25 of 33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.2708C>A	p.Thr903Lys	missense_variant, splice_region_variant	Exon 25 of 32	1	NM_015192.4	ENSP00000338185.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455376 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724414

African (AFR) AF: 0.00 AC: 0 AN: 33358

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106328

Other (OTH) AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1

Apr 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with lysine at codon 903 of the PLCB1 protein (p.Thr903Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PLCB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 538891). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	.;.;.;T;.;T;.;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;.;D;D;D;D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L;L;L;.;.;.
PhyloP100		5.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	.;.;N;N;N;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.35	.;.;T;T;T;.;.;.
Sift4G	Benign	0.45	.;T;T;T;T;T;T;T
Polyphen		0.046, 0.36	.;.;B;B;B;.;.;.
Vest4		0.50, 0.55, 0.50
MutPred		0.33		.;.;Gain of ubiquitination at T903 (P = 0.0051);Gain of ubiquitination at T903 (P = 0.0051);Gain of ubiquitination at T903 (P = 0.0051);.;.;.;
MVP		0.70
MPC		0.41
ClinPred		0.88	D
GERP RS		6.1
Varity_R		0.19
gMVP		0.22
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.79
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: rs775341189; hg19: chr20-8741105;