rs694353

chr11-85981138-A-Cchr11-85981138-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. A590A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.59 (26907 hom., cov: 33)
  • Exomes 𝑓: 0.58 (239128 hom.)
• Consequence: PICALM NM_007166.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.37

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]

ACMG classification

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	UniProt
PICALM	NM_007166.4	c.1770T>G	p.Ala590=	synonymous_variant	17/20	ENST00000393346.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PICALM	ENST00000393346.8	c.1770T>G	p.Ala590=	synonymous_variant	17/20	1	NM_007166.4

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90083 AN: 151998 Hom.: 26886 Cov.: 33

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

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.: 23 AF XY: 0.587 AC XY: 407591 AN XY: 694432

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.: 33 AF XY: 0.588 AC XY: 43744 AN XY: 74360

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	11
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

Other links and lift over

dbSNP: rs694353; hg19: chr11-85692181; COSMIC: COSV62671300; COSMIC: COSV62671300;