rs62465931

Variant names:

• chr7-82758644-G-A
• rs62465931
• NM_033026.6:c.15360C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_033026.6(PCLO):​c.15360C>T​(p.Asp5120Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.0195 in 1,611,034 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (34 hom., cov: 32)
  • Exomes 𝑓: 0.020 (324 hom.)
• Consequence: PCLO NM_033026.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.33
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 7-82758644-G-A is Benign according to our data. Variant chr7-82758644-G-A is described in ClinVar as Benign. ClinVar VariationId is 1600328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2525/151934) while in subpopulation NFE AF = 0.021 (1427/67864). AF 95% confidence interval is 0.0201. There are 34 homozygotes in GnomAd4. There are 1106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCLO	NM_033026.6	MANE Select	c.15360C>T	p.Asp5120Asp	synonymous	Exon 25 of 25	NP_149015.2	Q9Y6V0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCLO	ENST00000333891.14	TSL:2 MANE Select	c.15360C>T	p.Asp5120Asp	synonymous	Exon 25 of 25	ENSP00000334319.8	Q9Y6V0-5

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2520 AN: 151816 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0161 AC: 4011 AN: 248534 AF XY: 0.0166

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.00300

Gnomad FIN exome AF: 0.00377

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0198 AC: 28828 AN: 1459100 Hom.: 324 Cov.: 29 AF XY: 0.0195 AC XY: 14154 AN XY: 725968

African (AFR) AF: 0.0165 AC: 550 AN: 33386

American (AMR) AF: 0.00981 AC: 438 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 742 AN: 26048

East Asian (EAS) AF: 0.00356 AC: 141 AN: 39648

South Asian (SAS) AF: 0.0118 AC: 1014 AN: 86180

European-Finnish (FIN) AF: 0.00495 AC: 264 AN: 53308

Middle Eastern (MID) AF: 0.0366 AC: 211 AN: 5758

European-Non Finnish (NFE) AF: 0.0219 AC: 24253 AN: 1109844

Other (OTH) AF: 0.0202 AC: 1215 AN: 60262

GnomAD4 genome AF: 0.0166 AC: 2525 AN: 151934 Hom.: 34 Cov.: 32 AF XY: 0.0149 AC XY: 1106 AN XY: 74298

African (AFR) AF: 0.0150 AC: 623 AN: 41502

American (AMR) AF: 0.0105 AC: 160 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3464

East Asian (EAS) AF: 0.00407 AC: 21 AN: 5164

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10598

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0210 AC: 1427 AN: 67864

Other (OTH) AF: 0.0204 AC: 43 AN: 2106

Alfa AF: 0.0202 Hom.: 13

Bravo AF: 0.0174

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0222

EpiControl AF: 0.0221

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.3
DANN	Benign	0.66
PhyloP100		4.3
Mutation Taster		=95/5	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: rs62465931; hg19: chr7-82387960; COSMIC: COSV108151212;