rs10954696

chr7-82953530-C-T

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.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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8182 hom., cov: 29)
  • Exomes 𝑓: 0.37 (99562 hom.)
• Consequence: PCLO NM_033026.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27

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=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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCLO	NM_033026.6	c.7423G>A	p.Val2475Ile	missense_variant	5/25	ENST00000333891.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCLO	ENST00000333891.14	c.7423G>A	p.Val2475Ile	missense_variant	5/25	2	NM_033026.6	P1
PCLO	ENST00000423517.6	c.7423G>A	p.Val2475Ile	missense_variant	5/20	5

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46351 AN: 151158 Hom.: 8173 Cov.: 29

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

GnomAD3 exomes AF: 0.369 AC: 91943 AN: 248846 Hom.: 17701 AF XY: 0.372 AC XY: 50219 AN XY: 134986

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 SAS exome AF: 0.391

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.: 41 AF XY: 0.367 AC XY: 266747 AN XY: 726650

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.365

Gnomad4 EAS exome AF: 0.478

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.307 AC: 46372 AN: 151276 Hom.: 8182 Cov.: 29 AF XY: 0.312 AC XY: 23074 AN XY: 73854

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.368

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.326

Alfa AF: 0.355 Hom.: 24443

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.8
Dann	Benign	0.56
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.00033	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.097
Sift	Benign	0.42	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0010	.;B
Vest4		0.045
MPC		0.032
ClinPred		0.0010	T
GERP RS		2.6
Varity_R		0.026
gMVP		0.088

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

LitVar

Other links and lift over

dbSNP: rs10954696; hg19: chr7-82582846; COSMIC: COSV61620809; COSMIC: COSV61620809;