rs694353

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007166.4(PICALM):c.1770T>G(p.Ala590=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 1,539,134 control chromosomes in the GnomAD database, including 266,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 26907 hom., cov: 33)

Exomes 𝑓: 0.58 ( 239128 hom. )

Consequence

PICALM
NM_007166.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.37

Variant links:

Genes affected

PICALM (HGNC:15514): (phosphatidylinositol binding clathrin assembly protein) This gene encodes a clathrin assembly protein, which recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assembly. The protein may be required to determine the amount of membrane to be recycled, possibly by regulating the size of the clathrin cage. The protein is involved in AP2-dependent clathrin-mediated endocytosis at the neuromuscular junction. A chromosomal translocation t(10;11)(p13;q14) leading to the fusion of this gene and the MLLT10 gene is found in acute lymphoblastic leukemia, acute myeloid leukemia and malignant lymphomas. The polymorphisms of this gene are associated with the risk of Alzheimer disease. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

PICALM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 11-85981138-A-C is Benign according to our data. Variant chr11-85981138-A-C is described in ClinVar as [Benign]. Clinvar id is 403297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-85981138-A-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PICALM	NM_007166.4 linkuse as main transcript	c.1770T>G	p.Ala590=	synonymous_variant	17/20	ENST00000393346.8	NP_009097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PICALM	ENST00000393346.8 linkuse as main transcript	c.1770T>G	p.Ala590=	synonymous_variant	17/20	1	NM_007166.4	ENSP00000377015		Q13492-1

Frequencies

GnomAD3 genomes

AF:

0.593

AC:

90083

AN:

151998

Hom.:

26886

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.503

Gnomad AMR

AF:

0.623

Gnomad ASJ

AF:

0.492

Gnomad EAS

AF:

0.660

Gnomad SAS

AF:

0.661

Gnomad FIN

AF:

0.488

Gnomad MID

AF:

0.490

Gnomad NFE

AF:

0.588

Gnomad OTH

AF:

0.565

GnomAD3 exomes

AF:

0.597

AC:

149489

AN:

250604

Hom.:

45108

AF XY:

0.597

AC XY:

80852

AN XY:

135452

show subpopulations

Gnomad AFR exome

AF:

0.613

Gnomad AMR exome

AF:

0.644

Gnomad ASJ exome

AF:

0.491

Gnomad EAS exome

AF:

0.661

Gnomad SAS exome

AF:

0.655

Gnomad FIN exome

AF:

0.496

Gnomad NFE exome

AF:

0.582

Gnomad OTH exome

AF:

0.599

GnomAD4 exome

AF:

0.584

AC:

810694

AN:

1387018

Hom.:

239128

Cov.:

AF XY:

0.587

AC XY:

407591

AN XY:

694432

show subpopulations

Gnomad4 AFR exome

AF:

0.615

Gnomad4 AMR exome

AF:

0.638

Gnomad4 ASJ exome

AF:

0.492

Gnomad4 EAS exome

AF:

0.667

Gnomad4 SAS exome

AF:

0.650

Gnomad4 FIN exome

AF:

0.510

Gnomad4 NFE exome

AF:

0.579

Gnomad4 OTH exome

AF:

0.589

GnomAD4 genome

AF:

0.593

AC:

90155

AN:

152116

Hom.:

26907

Cov.:

AF XY:

0.588

AC XY:

43744

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.611

Gnomad4 AMR

AF:

0.623

Gnomad4 ASJ

AF:

0.492

Gnomad4 EAS

AF:

0.660

Gnomad4 SAS

AF:

0.663

Gnomad4 FIN

AF:

0.488

Gnomad4 NFE

AF:

0.588

Gnomad4 OTH

AF:

0.566

Alfa

AF:

0.561

Hom.:

9199

Bravo

AF:

0.599

EpiCase

AF:

0.585

EpiControl

AF:

0.580

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PICALM-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over