chr7-82952543-C-T

Variant names:

• chr7-82952543-C-T
• rs976714
• NM_033026.6:c.8410G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033026.6(PCLO):​c.8410G>A​(p.Ala2804Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,613,526 control chromosomes in the GnomAD database, including 107,846 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8222 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99624 hom.)
• Consequence: PCLO NM_033026.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.447
• Publications: 32 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=4.7973565E-5).
• BP6: Variant 7-82952543-C-T is Benign according to our data. Variant chr7-82952543-C-T is described in ClinVar as Benign. ClinVar VariationId is 1599232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCLO	NM_033026.6	c.8410G>A	p.Ala2804Thr	missense_variant	Exon 5 of 25	ENST00000333891.14	NP_149015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCLO	ENST00000333891.14	c.8410G>A	p.Ala2804Thr	missense_variant	Exon 5 of 25	2	NM_033026.6	ENSP00000334319.8
PCLO	ENST00000423517.6	c.8410G>A	p.Ala2804Thr	missense_variant	Exon 5 of 20	5		ENSP00000388393.2

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46608 AN: 151866 Hom.: 8213 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.370 AC: 92003 AN: 248980 AF XY: 0.372

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.496

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.366 AC: 535178 AN: 1461544 Hom.: 99624 Cov.: 59 AF XY: 0.367 AC XY: 267015 AN XY: 727066

African (AFR) AF: 0.123 AC: 4112 AN: 33470

American (AMR) AF: 0.406 AC: 18170 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 9544 AN: 26130

East Asian (EAS) AF: 0.476 AC: 18913 AN: 39694

South Asian (SAS) AF: 0.390 AC: 33639 AN: 86252

European-Finnish (FIN) AF: 0.391 AC: 20868 AN: 53400

Middle Eastern (MID) AF: 0.321 AC: 1849 AN: 5766

European-Non Finnish (NFE) AF: 0.366 AC: 406450 AN: 1111736

Other (OTH) AF: 0.358 AC: 21633 AN: 60372

GnomAD4 genome AF: 0.307 AC: 46629 AN: 151982 Hom.: 8222 Cov.: 32 AF XY: 0.313 AC XY: 23223 AN XY: 74278

African (AFR) AF: 0.131 AC: 5418 AN: 41498

American (AMR) AF: 0.373 AC: 5686 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1275 AN: 3470

East Asian (EAS) AF: 0.473 AC: 2430 AN: 5138

South Asian (SAS) AF: 0.389 AC: 1872 AN: 4814

European-Finnish (FIN) AF: 0.397 AC: 4189 AN: 10548

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24687 AN: 67944

Other (OTH) AF: 0.327 AC: 687 AN: 2102

Alfa AF: 0.348 Hom.: 43061

Bravo AF: 0.300

TwinsUK AF: 0.367 AC: 1359

ALSPAC AF: 0.355 AC: 1368

ESP6500AA AF: 0.138 AC: 565

ESP6500EA AF: 0.360 AC: 3018

ExAC AF: 0.361 AC: 43639

EpiCase AF: 0.358

EpiControl AF: 0.358

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.6
DANN	Benign	0.48
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.000048	T;T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.45
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.020
Sift	Benign	0.40	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0010	.;B
Vest4		0.012
MPC		0.036
ClinPred		0.00055	T
GERP RS		-5.0
Varity_R		0.037
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs976714; hg19: chr7-82581859; COSMIC: COSV61613903; COSMIC: COSV61613903;