7-82953530-C-T

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.7423G>A(p.Val2475Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,611,864 control chromosomes in the GnomAD database, including 107,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 8182 hom., cov: 29)

Exomes 𝑓: 0.37 ( 99562 hom. )

Consequence

PCLO
NM_033026.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.27

Publications

23 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=3.324747E-4).

BP6

Variant 7-82953530-C-T is Benign according to our data. Variant chr7-82953530-C-T is described in ClinVar as Benign. ClinVar VariationId is 1225294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033026.6. 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
	PCLO	NM_033026.6	MANE Select	c.7423G>A	p.Val2475Ile	missense	Exon 5 of 25	NP_149015.2
	PCLO	NM_014510.3		c.7423G>A	p.Val2475Ile	missense	Exon 5 of 20	NP_055325.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCLO	ENST00000333891.14	TSL:2 MANE Select	c.7423G>A	p.Val2475Ile	missense	Exon 5 of 25	ENSP00000334319.8
	PCLO	ENST00000423517.6	TSL:5	c.7423G>A	p.Val2475Ile	missense	Exon 5 of 20	ENSP00000388393.2

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46351

AN:

151158

Hom.:

8173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.368

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.387

Gnomad FIN

AF:

0.398

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.323

GnomAD2 exomes

AF:

0.369

AC:

91943

AN:

248846

AF XY:

0.372

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.359

Gnomad OTH exome

AF:

0.376

GnomAD4 exome

AF:

0.366

AC:

534561

AN:

1460588

Hom.:

99562

Cov.:

AF XY:

0.367

AC XY:

266747

AN XY:

726650

show subpopulations

African (AFR)

AF:

0.122

AC:

4081

AN:

33454

American (AMR)

AF:

0.406

AC:

18150

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

9523

AN:

26114

East Asian (EAS)

AF:

0.478

AC:

18969

AN:

39688

South Asian (SAS)

AF:

0.390

AC:

33626

AN:

86238

European-Finnish (FIN)

AF:

0.391

AC:

20869

AN:

53398

Middle Eastern (MID)

AF:

0.321

AC:

1851

AN:

5766

European-Non Finnish (NFE)

AF:

0.365

AC:

405882

AN:

1110868

Other (OTH)

AF:

0.358

AC:

21610

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

17905

35810

53714

71619

89524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12960

25920

38880

51840

64800

<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:

0.307

AC:

46372

AN:

151276

Hom.:

8182

Cov.:

AF XY:

0.312

AC XY:

23074

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.129

AC:

5336

AN:

41240

American (AMR)

AF:

0.372

AC:

5638

AN:

15170

Ashkenazi Jewish (ASJ)

AF:

0.368

AC:

1269

AN:

3452

East Asian (EAS)

AF:

0.477

AC:

2420

AN:

5076

South Asian (SAS)

AF:

0.387

AC:

1856

AN:

4790

European-Finnish (FIN)

AF:

0.398

AC:

4150

AN:

10438

Middle Eastern (MID)

AF:

0.301

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.363

AC:

24632

AN:

67806

Other (OTH)

AF:

0.326

AC:

684

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1486

2971

4457

5942

7428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.345

Hom.:

32244

Bravo

AF:

0.300

TwinsUK

AF:

0.366

AC:

1358

ALSPAC

AF:

0.355

AC:

1370

ESP6500AA

AF:

0.137

AC:

536

ESP6500EA

AF:

0.361

AC:

2995

ExAC

AF:

0.361

AC:

43617

Asia WGS

AF:

0.434

AC:

1508

AN:

3478

EpiCase

AF:

0.358

EpiControl

AF:

0.357

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.8

(source)

DANN

Benign

0.56

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.52

MetaRNN

Benign

0.00033

MetaSVM

Benign

-0.95

PhyloP100

-1.3

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.35

REVEL

Benign

0.097

Sift

Benign

0.42

Sift4G

Benign

0.47

Polyphen

0.0010

Vest4

0.045

MPC

0.032

ClinPred

0.0010

GERP RS

2.6

Varity_R

0.026

gMVP

0.088

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over