chr11-86007598-T-C

Position:

• chr11-86007598-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007166.4(PICALM):​c.766-15A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,306,846 control chromosomes in the GnomAD database, including 28,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2836 hom., cov: 32)
  • Exomes 𝑓: 0.21 (25688 hom.)
• Consequence: PICALM NM_007166.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.142

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 -16 ACMG points.

• BP6: Variant 11-86007598-T-C is Benign according to our data. Variant chr11-86007598-T-C is described in ClinVar as [Benign]. Clinvar id is 403298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86007598-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PICALM	NM_007166.4	c.766-15A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000393346.8	NP_009097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PICALM	ENST00000393346.8	c.766-15A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007166.4	ENSP00000377015

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27688 AN: 151990 Hom.: 2838 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.240 AC: 51024 AN: 212604 Hom.: 6687 AF XY: 0.238 AC XY: 27755 AN XY: 116700

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.535

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.206 AC: 238301 AN: 1154738 Hom.: 25688 Cov.: 16 AF XY: 0.209 AC XY: 122010 AN XY: 583468

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.460

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.182 AC: 27693 AN: 152108 Hom.: 2836 Cov.: 32 AF XY: 0.181 AC XY: 13467 AN XY: 74370

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.184

Alfa AF: 0.176 Hom.: 1348

Bravo AF: 0.183

Asia WGS AF: 0.333 AC: 1150 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Uncertain	23
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10792821; hg19: chr11-85718641;