11-86014894-C-T

Position:

• chr11-86014894-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_007166.4(PICALM):​c.522G>A​(p.Gln174Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,569,742 control chromosomes in the GnomAD database, including 499,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50869 hom., cov: 32)
  • Exomes 𝑓: 0.79 (449073 hom.)
• Consequence: PICALM NM_007166.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.238

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 11-86014894-C-T is Benign according to our data. Variant chr11-86014894-C-T is described in ClinVar as [Benign]. Clinvar id is 403299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86014894-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.238 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PICALM	NM_007166.4	c.522G>A	p.Gln174Gln	synonymous_variant	5/20	ENST00000393346.8	NP_009097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PICALM	ENST00000393346.8	c.522G>A	p.Gln174Gln	synonymous_variant	5/20	1	NM_007166.4	ENSP00000377015.3

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124082 AN: 152036 Hom.: 50826 Cov.: 32

Gnomad AFR AF: 0.889

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.802

Gnomad OTH AF: 0.791

GnomAD3 exomes AF: 0.779 AC: 186043 AN: 238928 Hom.: 72865 AF XY: 0.778 AC XY: 100543 AN XY: 129314

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.743

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.732

Gnomad FIN exome AF: 0.817

Gnomad NFE exome AF: 0.798

Gnomad OTH exome AF: 0.790

GnomAD4 exome AF: 0.795 AC: 1126620 AN: 1417588 Hom.: 449073 Cov.: 24 AF XY: 0.793 AC XY: 560746 AN XY: 707082

Gnomad4 AFR exome AF: 0.893

Gnomad4 AMR exome AF: 0.745

Gnomad4 ASJ exome AF: 0.741

Gnomad4 EAS exome AF: 0.696

Gnomad4 SAS exome AF: 0.735

Gnomad4 FIN exome AF: 0.820

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.792

GnomAD4 genome AF: 0.816 AC: 124182 AN: 152154 Hom.: 50869 Cov.: 32 AF XY: 0.813 AC XY: 60426 AN XY: 74362

Gnomad4 AFR AF: 0.889

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.751

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.733

Gnomad4 FIN AF: 0.821

Gnomad4 NFE AF: 0.802

Gnomad4 OTH AF: 0.789

Alfa AF: 0.798 Hom.: 21729

Bravo AF: 0.814

Asia WGS AF: 0.701 AC: 2438 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 28171541) -
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 16, 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	-0.40
CADD	Benign	5.2
DANN	Benign	0.65

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: rs592297; hg19: chr11-85725937; COSMIC: COSV62672141;