rs2522833

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033026.6(PCLO):c.14440T>G(p.Ser4814Ala) variant causes a missense change. The variant allele was found at a frequency of 0.432 in 1,603,872 control chromosomes in the GnomAD database, including 157,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 11566 hom., cov: 29)

Exomes 𝑓: 0.44 ( 145889 hom. )

Consequence

PCLO
NM_033026.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.23

Publications

79 publications found

Variant links:

Genes affected

PCLO (HGNC:13406): (piccolo presynaptic cytomatrix protein) The protein encoded by this gene is part of the presynaptic cytoskeletal matrix, which is involved in establishing active synaptic zones and in synaptic vesicle trafficking. Variations in this gene have been associated with bipolar disorder and major depressive disorder. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

PCLO Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 3
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

PCLO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.663249E-6).

BP6

Variant 7-82824392-A-C is Benign according to our data. Variant chr7-82824392-A-C is described in ClinVar as Benign. ClinVar VariationId is 1284557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCLO	NM_033026.6 link	c.14440T>G	p.Ser4814Ala	missense_variant	Exon 19 of 25	ENST00000333891.14	NP_149015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCLO	ENST00000333891.14 link	c.14440T>G	p.Ser4814Ala	missense_variant	Exon 19 of 25	2	NM_033026.6	ENSP00000334319.8
PCLO	ENST00000426442.6 link	n.935T>G		non_coding_transcript_exon_variant	Exon 10 of 11	1
PCLO	ENST00000423517.6 link	c.14440T>G	p.Ser4814Ala	missense_variant	Exon 19 of 20	5		ENSP00000388393.2
PCLO	ENST00000618073.1 link	c.703T>G	p.Ser235Ala	missense_variant	Exon 9 of 10	5		ENSP00000482390.1

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53134

AN:

151330

Hom.:

11556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.417

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.696

Gnomad SAS

AF:

0.565

Gnomad FIN

AF:

0.470

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.428

Gnomad OTH

AF:

0.368

GnomAD2 exomes

AF:

0.452

AC:

111481

AN:

246548

AF XY:

0.461

show subpopulations

Gnomad AFR exome

AF:

0.0895

Gnomad AMR exome

AF:

0.453

Gnomad ASJ exome

AF:

0.414

Gnomad EAS exome

AF:

0.704

Gnomad FIN exome

AF:

0.473

Gnomad NFE exome

AF:

0.426

Gnomad OTH exome

AF:

0.440

GnomAD4 exome

AF:

0.440

AC:

639580

AN:

1452426

Hom.:

145889

Cov.:

AF XY:

0.445

AC XY:

321626

AN XY:

722856

show subpopulations

African (AFR)

AF:

0.0898

AC:

2987

AN:

33266

American (AMR)

AF:

0.445

AC:

19696

AN:

44268

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

10498

AN:

25944

East Asian (EAS)

AF:

0.652

AC:

25836

AN:

39604

South Asian (SAS)

AF:

0.574

AC:

49184

AN:

85618

European-Finnish (FIN)

AF:

0.474

AC:

25261

AN:

53332

Middle Eastern (MID)

AF:

0.436

AC:

2406

AN:

5524

European-Non Finnish (NFE)

AF:

0.433

AC:

477981

AN:

1104858

Other (OTH)

AF:

0.429

AC:

25731

AN:

60012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

14428

28856

43285

57713

72141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14698

29396

44094

58792

73490

<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:

0.351

AC:

53155

AN:

151446

Hom.:

11566

Cov.:

AF XY:

0.359

AC XY:

26541

AN XY:

73954

show subpopulations

African (AFR)

AF:

0.100

AC:

4152

AN:

41336

American (AMR)

AF:

0.404

AC:

6121

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1374

AN:

3466

East Asian (EAS)

AF:

0.698

AC:

3577

AN:

5128

South Asian (SAS)

AF:

0.567

AC:

2697

AN:

4760

European-Finnish (FIN)

AF:

0.470

AC:

4910

AN:

10456

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.428

AC:

29051

AN:

67848

Other (OTH)

AF:

0.368

AC:

775

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1502

3004

4505

6007

7509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

524

1048

1572

2096

2620

<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:

0.403

Hom.:

47037

Bravo

AF:

0.334

TwinsUK

AF:

0.434

AC:

1608

ALSPAC

AF:

0.426

AC:

1642

ESP6500AA

AF:

0.103

AC:

394

ESP6500EA

AF:

0.419

AC:

3466

ExAC

AF:

0.442

AC:

53417

Asia WGS

AF:

0.600

AC:

2084

AN:

3478

EpiCase

AF:

0.417

EpiControl

AF:

0.414

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pontocerebellar hypoplasia type 3

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.081

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.53

T;T;T

MetaRNN

Benign

0.0000067

T;T;T

MetaSVM

Benign

-0.97

PhyloP100

4.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.85

N;N;.

REVEL

Benign

0.096

Sift

Benign

0.32

T;T;.

Sift4G

Benign

0.71

T;T;T

Polyphen

0.013, 0.0

.;B;B

Vest4

0.45

MPC

0.033

ClinPred

0.015

GERP RS

5.7

Varity_R

0.20

gMVP

0.13

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over