20-8132482-C-A

Variant names:

• chr20-8132482-C-A
• rs139962835
• NM_015192.4:c.-170C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015192.4(PLCB1):​c.-170C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 354,066 control chromosomes in the GnomAD database, including 425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (148 hom., cov: 32)
  • Exomes 𝑓: 0.046 (277 hom.)
• Consequence: PLCB1 NM_015192.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.360
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 20-8132482-C-A is Benign according to our data. Variant chr20-8132482-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 897294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.-170C>A		5_prime_UTR_variant	Exon 1 of 32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.-170C>A		5_prime_UTR_variant	Exon 1 of 33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.-170C>A		5_prime_UTR_variant	Exon 1 of 32	1	NM_015192.4	ENSP00000338185.6

Frequencies

GnomAD3 genomes AF: 0.0395 AC: 5982 AN: 151564 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0487

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.0994

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0505

GnomAD4 exome AF: 0.0460 AC: 9320 AN: 202392 Hom.: 277 Cov.: 3 AF XY: 0.0472 AC XY: 4917 AN XY: 104156

African (AFR) AF: 0.0347 AC: 176 AN: 5070

American (AMR) AF: 0.0504 AC: 276 AN: 5472

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 725 AN: 6652

East Asian (EAS) AF: 0.00 AC: 0 AN: 17430

South Asian (SAS) AF: 0.0294 AC: 78 AN: 2650

European-Finnish (FIN) AF: 0.0249 AC: 540 AN: 21712

Middle Eastern (MID) AF: 0.0902 AC: 90 AN: 998

European-Non Finnish (NFE) AF: 0.0522 AC: 6784 AN: 130008

Other (OTH) AF: 0.0525 AC: 651 AN: 12400

GnomAD4 genome AF: 0.0394 AC: 5982 AN: 151674 Hom.: 148 Cov.: 32 AF XY: 0.0381 AC XY: 2828 AN XY: 74130

African (AFR) AF: 0.0326 AC: 1349 AN: 41408

American (AMR) AF: 0.0485 AC: 740 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 309 AN: 3468

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5070

South Asian (SAS) AF: 0.0214 AC: 103 AN: 4816

European-Finnish (FIN) AF: 0.0175 AC: 185 AN: 10550

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 290

European-Non Finnish (NFE) AF: 0.0460 AC: 3119 AN: 67810

Other (OTH) AF: 0.0495 AC: 104 AN: 2100

Alfa AF: 0.0423 Hom.: 14

Bravo AF: 0.0417

Asia WGS AF: 0.0140 AC: 49 AN: 3446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 12 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		0.36
PromoterAI		-0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=299/1	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: rs139962835; hg19: chr20-8113129;