rs2522833

chr7-82824392-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.23

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1284557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-82824392-A-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PCLO	NM_033026.6	c.14440T>G	p.Ser4814Ala	missense_variant	19/25	ENST00000333891.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCLO	ENST00000333891.14	c.14440T>G	p.Ser4814Ala	missense_variant	19/25	2	NM_033026.6	P1
PCLO	ENST00000426442.6	n.935T>G		non_coding_transcript_exon_variant	10/11	1
PCLO	ENST00000423517.6	c.14440T>G	p.Ser4814Ala	missense_variant	19/20	5
PCLO	ENST00000618073.1	c.703T>G	p.Ser235Ala	missense_variant	9/10	5

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53134 AN: 151330 Hom.: 11556 Cov.: 29

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

GnomAD3 exomes AF: 0.452 AC: 111481 AN: 246548 Hom.: 27156 AF XY: 0.461 AC XY: 61624 AN XY: 133656

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 SAS exome AF: 0.582

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.: 30 AF XY: 0.445 AC XY: 321626 AN XY: 722856

Gnomad4 AFR exome AF: 0.0898

Gnomad4 AMR exome AF: 0.445

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.652

Gnomad4 SAS exome AF: 0.574

Gnomad4 FIN exome AF: 0.474

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.351 AC: 53155 AN: 151446 Hom.: 11566 Cov.: 29 AF XY: 0.359 AC XY: 26541 AN XY: 73954

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.567

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.368

Alfa AF: 0.416 Hom.: 34024

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Pontocerebellar hypoplasia type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	22
Dann	Benign	0.95
Eigen	Benign	-0.081
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.0000067	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.0060	P;P
PrimateAI	Uncertain	0.61	T
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	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs2522833; hg19: chr7-82453708; COSMIC: COSV61620784; COSMIC: COSV61620784;