7-82953681-G-T

Variant names:

• chr7-82953681-G-T
• rs1060499888
• NM_033026.6:c.7272C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000333891.14(PCLO):​c.7272C>A​(p.Pro2424Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,154,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P2424P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PCLO ENST00000333891.14 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.596
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=-0.596 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000333891.14. 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.7272C>A	p.Pro2424Pro	synonymous	Exon 5 of 25	NP_149015.2
	PCLO	NM_014510.3		c.7272C>A	p.Pro2424Pro	synonymous	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.7272C>A	p.Pro2424Pro	synonymous	Exon 5 of 25	ENSP00000334319.8
	PCLO	ENST00000423517.6	TSL:5	c.7272C>A	p.Pro2424Pro	synonymous	Exon 5 of 20	ENSP00000388393.2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000346 AC: 4 AN: 1154488 Hom.: 0 Cov.: 21 AF XY: 0.00000173 AC XY: 1 AN XY: 577480

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27010

American (AMR) AF: 0.00 AC: 0 AN: 34496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21978

East Asian (EAS) AF: 0.00 AC: 0 AN: 34358

South Asian (SAS) AF: 0.00 AC: 0 AN: 70424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3754

European-Non Finnish (NFE) AF: 0.00000458 AC: 4 AN: 874206

Other (OTH) AF: 0.00 AC: 0 AN: 49996

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.52
DANN	Benign	0.54
PhyloP100		-0.60

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: rs1060499888; hg19: chr7-82582997;