rs2076413

Variant names:

• chr20-8757087-G-A
• rs2076413
• NM_015192.4:c.2565G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-8757087-G-A
• chr20-8757087-G-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.2565G>A​(p.Ala855Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,611,358 control chromosomes in the GnomAD database, including 71,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A855A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5232 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66464 hom.)
• Consequence: PLCB1 NM_015192.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.138
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 20-8757087-G-A is Benign according to our data. Variant chr20-8757087-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.138 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 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.2565G>A	p.Ala855Ala	synonymous	Exon 24 of 32	NP_056007.1	Q9NQ66-1
	PLCB1	NM_182734.3		c.2565G>A	p.Ala855Ala	synonymous	Exon 24 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.2565G>A	p.Ala855Ala	synonymous	Exon 24 of 32	ENSP00000338185.6	Q9NQ66-1
	PLCB1	ENST00000378637.6	TSL:1	c.2565G>A	p.Ala855Ala	synonymous	Exon 24 of 32	ENSP00000367904.2	Q9NQ66-2
	PLCB1	ENST00000378641.7	TSL:1	c.2565G>A	p.Ala855Ala	synonymous	Exon 24 of 33	ENSP00000367908.3	Q9NQ66-2

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37699 AN: 151880 Hom.: 5232 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.270 AC: 67806 AN: 250748 AF XY: 0.278

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.298 AC: 434946 AN: 1459360 Hom.: 66464 Cov.: 32 AF XY: 0.300 AC XY: 217684 AN XY: 726034

African (AFR) AF: 0.129 AC: 4325 AN: 33450

American (AMR) AF: 0.199 AC: 8863 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7920 AN: 26098

East Asian (EAS) AF: 0.155 AC: 6165 AN: 39666

South Asian (SAS) AF: 0.302 AC: 26000 AN: 85958

European-Finnish (FIN) AF: 0.289 AC: 15425 AN: 53362

Middle Eastern (MID) AF: 0.228 AC: 1313 AN: 5754

European-Non Finnish (NFE) AF: 0.313 AC: 347751 AN: 1110134

Other (OTH) AF: 0.285 AC: 17184 AN: 60290

GnomAD4 genome AF: 0.248 AC: 37707 AN: 151998 Hom.: 5232 Cov.: 32 AF XY: 0.247 AC XY: 18371 AN XY: 74268

African (AFR) AF: 0.135 AC: 5592 AN: 41466

American (AMR) AF: 0.217 AC: 3321 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 963 AN: 3468

East Asian (EAS) AF: 0.154 AC: 796 AN: 5156

South Asian (SAS) AF: 0.309 AC: 1489 AN: 4814

European-Finnish (FIN) AF: 0.299 AC: 3156 AN: 10544

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21641 AN: 67960

Other (OTH) AF: 0.231 AC: 488 AN: 2114

Alfa AF: 0.290 Hom.: 10232

Bravo AF: 0.235

Asia WGS AF: 0.230 AC: 802 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.313

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Developmental and epileptic encephalopathy, 12 (4)
-	-	4	not specified (4)
-	-	3	not provided (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	-0.55
CADD	Benign	7.5
DANN	Benign	0.39
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs2076413; hg19: chr20-8737734; COSMIC: COSV62038835; COSMIC: COSV62038835;