chr20-8774596-T-C

Variant names:

• chr20-8774596-T-C
• rs2235613
• NM_015192.4:c.2988T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015192.4(PLCB1):​c.2988T>C​(p.Ala996Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,613,212 control chromosomes in the GnomAD database, including 322,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30290 hom., cov: 32)
  • Exomes 𝑓: 0.63 (291715 hom.)
• Consequence: PLCB1 NM_015192.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.931
• Publications: 29 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 20-8774596-T-C is Benign according to our data. Variant chr20-8774596-T-C is described in ClinVar as Benign. ClinVar VariationId is 129910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.931 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

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.2988T>C	p.Ala996Ala	synonymous	Exon 27 of 32	NP_056007.1
	PLCB1	NM_182734.3		c.2988T>C	p.Ala996Ala	synonymous	Exon 27 of 33	NP_877398.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	ENST00000338037.11	TSL:1 MANE Select	c.2988T>C	p.Ala996Ala	synonymous	Exon 27 of 32	ENSP00000338185.6
	PLCB1	ENST00000378637.6	TSL:1	c.2988T>C	p.Ala996Ala	synonymous	Exon 27 of 32	ENSP00000367904.2
	PLCB1	ENST00000378641.7	TSL:1	c.2988T>C	p.Ala996Ala	synonymous	Exon 27 of 33	ENSP00000367908.3

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95395 AN: 151952 Hom.: 30263 Cov.: 32

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.756

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.640

GnomAD2 exomes AF: 0.607 AC: 152629 AN: 251346 AF XY: 0.620

Gnomad AFR exome AF: 0.641

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.629 AC: 919303 AN: 1461142 Hom.: 291715 Cov.: 43 AF XY: 0.634 AC XY: 460573 AN XY: 726860

African (AFR) AF: 0.646 AC: 21629 AN: 33474

American (AMR) AF: 0.442 AC: 19768 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 18902 AN: 26122

East Asian (EAS) AF: 0.515 AC: 20455 AN: 39700

South Asian (SAS) AF: 0.738 AC: 63599 AN: 86158

European-Finnish (FIN) AF: 0.561 AC: 29955 AN: 53400

Middle Eastern (MID) AF: 0.696 AC: 4017 AN: 5768

European-Non Finnish (NFE) AF: 0.632 AC: 702094 AN: 1111428

Other (OTH) AF: 0.644 AC: 38884 AN: 60368

GnomAD4 genome AF: 0.628 AC: 95469 AN: 152070 Hom.: 30290 Cov.: 32 AF XY: 0.625 AC XY: 46493 AN XY: 74336

African (AFR) AF: 0.643 AC: 26679 AN: 41460

American (AMR) AF: 0.555 AC: 8484 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2474 AN: 3472

East Asian (EAS) AF: 0.504 AC: 2609 AN: 5176

South Asian (SAS) AF: 0.756 AC: 3646 AN: 4820

European-Finnish (FIN) AF: 0.568 AC: 6004 AN: 10574

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43406 AN: 67966

Other (OTH) AF: 0.643 AC: 1357 AN: 2112

Alfa AF: 0.632 Hom.: 114739

Bravo AF: 0.618

Asia WGS AF: 0.632 AC: 2198 AN: 3478

EpiCase AF: 0.649

EpiControl AF: 0.658

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Developmental and epileptic encephalopathy, 12 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Early Infantile Epileptic Encephalopathy, Autosomal Recessive (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.7
DANN	Benign	0.60
PhyloP100		-0.93
Mutation Taster		=97/3	polymorphism (auto)

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: rs2235613; hg19: chr20-8755243; COSMIC: COSV62038851;