rs28390202

Variant names:

• chr20-8881748-C-T
• rs28390202
• NM_015192.4:c.3550C>T

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.3550C>T​(p.Leu1184Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00411 in 1,614,034 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. L1184L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (16 hom.)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 0.170
• Publications: 8 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=0.0044052005).
• BP6: Variant 20-8881748-C-T is Benign according to our data. Variant chr20-8881748-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95688.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (394/152262) while in subpopulation NFE AF = 0.00462 (314/68022). AF 95% confidence interval is 0.0042. There are 2 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.3550C>T	p.Leu1184Phe	missense	Exon 32 of 32	NP_056007.1	Q9NQ66-1
	PLCB1	NM_182734.3		c.*146C>T		3_prime_UTR	Exon 33 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.3550C>T	p.Leu1184Phe	missense	Exon 32 of 32	ENSP00000338185.6	Q9NQ66-1
	PLCB1	ENST00000378641.7	TSL:1	c.*146C>T		3_prime_UTR	Exon 33 of 33	ENSP00000367908.3	Q9NQ66-2
	PLCB1	ENST00000487210.5	TSL:1	n.*19+79575C>T		intron	N/A	ENSP00000431704.1	H0YCJ2

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00259 AC: 651 AN: 251264 AF XY: 0.00267

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00427 AC: 6243 AN: 1461772 Hom.: 16 Cov.: 31 AF XY: 0.00415 AC XY: 3020 AN XY: 727194

African (AFR) AF: 0.000538 AC: 18 AN: 33478

American (AMR) AF: 0.00157 AC: 70 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.00204 AC: 109 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00525 AC: 5843 AN: 1111902

Other (OTH) AF: 0.00288 AC: 174 AN: 60392

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74440

African (AFR) AF: 0.000939 AC: 39 AN: 41548

American (AMR) AF: 0.00124 AC: 19 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00367 Hom.: 3

Bravo AF: 0.00257

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	3	Developmental and epileptic encephalopathy, 12 (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	PLCB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.17
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.092
Sift	Benign	0.035	D
Sift4G	Benign	0.072	T
Polyphen		0.0060	B
Vest4		0.010
MVP		0.11
MPC		0.34
ClinPred		0.0017	T
GERP RS		-0.69
Varity_R		0.066
gMVP		0.035
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28390202; hg19: chr20-8862395;