20-9409079-C-T

Variant names:

• chr20-9409079-C-T
• rs397514482
• NM_001377142.1:c.1897C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001377142.1(PLCB4):​c.1897C>T​(p.Arg633Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 152,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633L) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: PLCB4 NM_001377142.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.10
• Publications: 7 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: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-9409080-G-T is described in CliVar as Pathogenic. Clinvar id is 64692.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 20-9409079-C-T is Pathogenic according to our data. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9409079-C-T is described in CliVar as Pathogenic. Clinvar id is 31640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB4	NM_001377142.1	c.1897C>T	p.Arg633Cys	missense_variant	Exon 24 of 40	ENST00000378473.9	NP_001364071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB4	ENST00000378473.9	c.1897C>T	p.Arg633Cys	missense_variant	Exon 24 of 40	1	NM_001377142.1	ENSP00000367734.5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74240

African (AFR) AF: 0.0000242 AC: 1 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 621 of the PLCB4 protein (p.Arg621Cys). This variant is present in population databases (rs397514482, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant auriculocondylar syndrome (PMID: 22560091, 35170830). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 31640). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PLCB4 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg621 amino acid residue in PLCB4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22560091). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 22, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22560091, 35170830, 18314001, 23315542) -

Auriculocondylar syndrome 2 Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Auriculocondylar syndrome 1 Pathogenic:1

Sep 17, 2012

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	.;H;.;H;H
PhyloP100		6.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.9	D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;D;D
Vest4		0.94
MutPred		0.88		.;Loss of MoRF binding (P = 6e-04);.;Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.95
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs397514482; hg19: chr20-9389726; COSMIC: COSV99595451;