rs61755436

Variant names:

• chr20-8788457-A-G
• rs61755436
• NM_015192.4:c.3120A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015192.4(PLCB1):​c.3120A>G​(p.Gln1040Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,110 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (64 hom.)
• Consequence: PLCB1 NM_015192.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.958
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 20-8788457-A-G is Benign according to our data. Variant chr20-8788457-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00223 (340/152344) while in subpopulation AMR AF = 0.0197 (301/15302). AF 95% confidence interval is 0.0178. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB1	NM_015192.4	MANE Select	c.3120A>G	p.Gln1040Gln	synonymous	Exon 28 of 32	NP_056007.1	Q9NQ66-1
	PLCB1	NM_182734.3		c.3120A>G	p.Gln1040Gln	synonymous	Exon 28 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.3120A>G	p.Gln1040Gln	synonymous	Exon 28 of 32	ENSP00000338185.6	Q9NQ66-1
	PLCB1	ENST00000378637.6	TSL:1	c.3120A>G	p.Gln1040Gln	synonymous	Exon 28 of 32	ENSP00000367904.2	Q9NQ66-2
	PLCB1	ENST00000378641.7	TSL:1	c.3120A>G	p.Gln1040Gln	synonymous	Exon 28 of 33	ENSP00000367908.3	Q9NQ66-2

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 341 AN: 152226 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00764 AC: 1907 AN: 249662 AF XY: 0.00573

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00161 AC: 2349 AN: 1460766 Hom.: 64 Cov.: 31 AF XY: 0.00132 AC XY: 959 AN XY: 726548

African (AFR) AF: 0.0000598 AC: 2 AN: 33454

American (AMR) AF: 0.0489 AC: 2180 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39640

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111670

Other (OTH) AF: 0.00124 AC: 75 AN: 60362

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152344 Hom.: 2 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74500

African (AFR) AF: 0.000289 AC: 12 AN: 41584

American (AMR) AF: 0.0197 AC: 301 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000850 Hom.: 1

Bravo AF: 0.00496

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Developmental and epileptic encephalopathy, 12 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	PLCB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.4
DANN	Benign	0.57
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61755436; hg19: chr20-8769104;