rs193921109

Variant names:

• chr20-9362934-C-A
• rs193921109
• NM_001377142.1:c.408C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001377142.1(PLCB4):​c.408C>A​(p.Phe136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLCB4 NM_001377142.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.94
• Publications: 1 publications found

Genes affected

PLCB4 (HGNC:9059): (phospholipase C beta 4) 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 in the retina. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2010]

PLCB4 Gene-Disease associations (from GenCC):

• auriculocondylar syndrome 2

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
• auriculocondylar syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4029398).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377142.1. 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
	PLCB4	NM_001377142.1	MANE Select	c.408C>A	p.Phe136Leu	missense	Exon 8 of 40	NP_001364071.1
	PLCB4	NM_001377143.1		c.408C>A	p.Phe136Leu	missense	Exon 7 of 39	NP_001364072.1
	PLCB4	NM_000933.4		c.408C>A	p.Phe136Leu	missense	Exon 8 of 39	NP_000924.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB4	ENST00000378473.9	TSL:1 MANE Select	c.408C>A	p.Phe136Leu	missense	Exon 8 of 40	ENSP00000367734.5
	PLCB4	ENST00000278655.9	TSL:1	c.408C>A	p.Phe136Leu	missense	Exon 7 of 36	ENSP00000278655.5
	PLCB4	ENST00000946820.1		c.408C>A	p.Phe136Leu	missense	Exon 8 of 40	ENSP00000616879.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.23	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.22
Sift	Benign	0.86	T
Sift4G	Benign	1.0	T
Polyphen		0.92	P
Vest4		0.66
MutPred		0.40		Gain of catalytic residue at F136 (P = 0.0479)
MVP		0.42
MPC		0.88
ClinPred		0.85	D
GERP RS		4.9
Varity_R		0.066
gMVP		0.45
Mutation Taster		=63/37	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: rs193921109; hg19: chr20-9343581; COSMIC: COSV53797177;