rs75820839

Variant names:

• chr20-8788453-T-C
• rs75820839
• NM_015192.4:c.3116T>C

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.3116T>C​(p.Ile1039Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,612,872 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1039L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: PLCB1 NM_015192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 7.61
• Publications: 2 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=0.009486049).
• BP6: Variant 20-8788453-T-C is Benign according to our data. Variant chr20-8788453-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235385.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00234 (357/152352) while in subpopulation AFR AF = 0.00825 (343/41590). AF 95% confidence interval is 0.00753. There are 1 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	NM_015192.4	MANE Select	c.3116T>C	p.Ile1039Thr	missense	Exon 28 of 32	NP_056007.1
	PLCB1	NM_182734.3		c.3116T>C	p.Ile1039Thr	missense	Exon 28 of 33	NP_877398.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	ENST00000338037.11	TSL:1 MANE Select	c.3116T>C	p.Ile1039Thr	missense	Exon 28 of 32	ENSP00000338185.6
	PLCB1	ENST00000378637.6	TSL:1	c.3116T>C	p.Ile1039Thr	missense	Exon 28 of 32	ENSP00000367904.2
	PLCB1	ENST00000378641.7	TSL:1	c.3116T>C	p.Ile1039Thr	missense	Exon 28 of 33	ENSP00000367908.3

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152234 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000726 AC: 181 AN: 249230 AF XY: 0.000543

Gnomad AFR exome AF: 0.00864

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000301 AC: 439 AN: 1460520 Hom.: 3 Cov.: 31 AF XY: 0.000281 AC XY: 204 AN XY: 726366

African (AFR) AF: 0.00879 AC: 294 AN: 33448

American (AMR) AF: 0.000539 AC: 24 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000702 AC: 78 AN: 1111604

Other (OTH) AF: 0.000646 AC: 39 AN: 60350

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152352 Hom.: 1 Cov.: 33 AF XY: 0.00212 AC XY: 158 AN XY: 74500

African (AFR) AF: 0.00825 AC: 343 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68038

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000895 Hom.: 1

Bravo AF: 0.00273

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000799 AC: 97

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Developmental and epileptic encephalopathy, 12 (2)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.33	T
Sift4G	Benign	0.34	T
Polyphen		0.0040	B
Vest4		0.70
MVP		0.34
MPC		0.41
ClinPred		0.032	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.053
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs75820839; hg19: chr20-8769100;