20-9307875-G-C

Variant names:

• chr20-9307875-G-C
• rs6077510
• NM_001377142.1:c.61G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001377142.1(PLCB4):​c.61G>C​(p.Ala21Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLCB4 NM_001377142.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.01
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB4	NM_001377142.1	MANE Select	c.61G>C	p.Ala21Pro	missense	Exon 4 of 40	NP_001364071.1
	PLCB4	NM_001377143.1		c.61G>C	p.Ala21Pro	missense	Exon 3 of 39	NP_001364072.1
	PLCB4	NM_000933.4		c.61G>C	p.Ala21Pro	missense	Exon 4 of 39	NP_000924.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB4	ENST00000378473.9	TSL:1 MANE Select	c.61G>C	p.Ala21Pro	missense	Exon 4 of 40	ENSP00000367734.5
	PLCB4	ENST00000278655.9	TSL:1	c.61G>C	p.Ala21Pro	missense	Exon 3 of 36	ENSP00000278655.5
	PLCB4	ENST00000946820.1		c.61G>C	p.Ala21Pro	missense	Exon 4 of 40	ENSP00000616879.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.25
Sift	Benign	0.043	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.45		Gain of disorder (P = 0.071)
MVP		0.64
MPC		1.8
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.57
gMVP		0.71
Mutation Taster		=62/38	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: rs6077510; hg19: chr20-9288522;