rs45608240

Variant names:

• chr20-8717804-A-G
• rs45608240
• NM_015192.4:c.1469A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015192.4(PLCB1):​c.1469A>G​(p.Tyr490Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,613,838 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y490Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (24 hom.)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.25
• Publications: 11 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005054921).
• BP6: Variant 20-8717804-A-G is Benign according to our data. Variant chr20-8717804-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129902.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00376 (572/152298) while in subpopulation NFE AF = 0.00644 (438/68030). AF 95% confidence interval is 0.00594. There are 1 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015192.4. 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
	PLCB1	NM_015192.4	MANE Select	c.1469A>G	p.Tyr490Cys	missense	Exon 14 of 32	NP_056007.1	Q9NQ66-1
	PLCB1	NM_182734.3		c.1469A>G	p.Tyr490Cys	missense	Exon 14 of 33	NP_877398.1	Q9NQ66-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	ENST00000338037.11	TSL:1 MANE Select	c.1469A>G	p.Tyr490Cys	missense	Exon 14 of 32	ENSP00000338185.6	Q9NQ66-1
	PLCB1	ENST00000378637.6	TSL:1	c.1469A>G	p.Tyr490Cys	missense	Exon 14 of 32	ENSP00000367904.2	Q9NQ66-2
	PLCB1	ENST00000378641.7	TSL:1	c.1469A>G	p.Tyr490Cys	missense	Exon 14 of 33	ENSP00000367908.3	Q9NQ66-2

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00644

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00354 AC: 887 AN: 250292 AF XY: 0.00351

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00580

Gnomad OTH exome AF: 0.00476

GnomAD4 exome AF: 0.00607 AC: 8871 AN: 1461540 Hom.: 24 Cov.: 31 AF XY: 0.00588 AC XY: 4276 AN XY: 727056

African (AFR) AF: 0.000598 AC: 20 AN: 33456

American (AMR) AF: 0.00282 AC: 126 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39686

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86222

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53370

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.00728 AC: 8099 AN: 1111864

Other (OTH) AF: 0.00573 AC: 346 AN: 60388

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74484

African (AFR) AF: 0.00132 AC: 55 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00644 AC: 438 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00500 Hom.: 5

Bravo AF: 0.00401

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00353 AC: 429

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00558

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 12 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Early Infantile Epileptic Encephalopathy, Autosomal Recessive (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	PLCB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.69
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.32
MPC		1.3
ClinPred		0.0058	T
GERP RS		-1.8
Varity_R		0.061
gMVP		0.24
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45608240; hg19: chr20-8698451; COSMIC: COSV99059812;