chr12-18699796-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033123.4(PLCZ1):c.1172G>A(p.Arg391Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PLCZ1
NM_033123.4 missense, splice_region

Scores

Splicing: ADA: 0.000009889

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.47

Publications

4 publications found

Variant links:

Genes affected

PLCZ1 (HGNC:19218): (phospholipase C zeta 1) The protein encoded by this gene is a member of the phosphoinositide-specific phospholipase C family. Members in this family, classified into six isotypes that are tissue- and organ-specific, hydrolyze phosphatidylinositol 4,5-bisphosphate just before the phosphate group to yield diacylglycerol and inositol 1,4,5-trisphosphate. This protein localizes to the acrosome in spermatozoa and elicits Ca(2+) oscillations and egg activation during fertilization that leads to early embryonic development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

PLCZ1 links:

PIK3C2G (HGNC:8973): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma) The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

PIK3C2G links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05713001).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCZ1	NM_033123.4	MANE Select	c.1172G>A	p.Arg391Gln	missense splice_region	Exon 10 of 15	NP_149114.2
PLCZ1	NM_001330774.2		c.860G>A	p.Arg287Gln	missense splice_region	Exon 10 of 15	NP_001317703.1	Q86YW0-3
PLCZ1	NM_001330769.1		c.593G>A	p.Arg198Gln	missense splice_region	Exon 6 of 11	NP_001317698.1	Q86YW0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCZ1	ENST00000266505.12	TSL:1 MANE Select	c.1172G>A	p.Arg391Gln	missense splice_region	Exon 10 of 15	ENSP00000266505.7	Q86YW0-1
PLCZ1	ENST00000648272.1		c.1295G>A	p.Arg432Gln	missense splice_region	Exon 9 of 14	ENSP00000497636.1	A0A3B3ISW9
PLCZ1	ENST00000539875.5	TSL:1	c.593G>A	p.Arg198Gln	missense splice_region	Exon 6 of 11	ENSP00000445026.1	Q86YW0-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250716

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460840

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111324

Other (OTH)

AF:

0.0000166

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.061

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.73

M_CAP

Benign

0.020

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.12

PhyloP100

-1.5

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.51

REVEL

Benign

0.13

Sift

Benign

0.29

Sift4G

Benign

0.31

Polyphen

0.15

Vest4

0.33

MutPred

0.54

Gain of catalytic residue at E394 (P = 0.0184)

MVP

0.17

MPC

0.019

ClinPred

0.029

GERP RS

-12

Varity_R

0.035

gMVP

0.13

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000099

dbscSNV1_RF

Benign

0.020

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over