rs642949

chr11-86018329-A-Gchr11-86018329-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007166.4(PICALM):c.453-3366T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 152,030 control chromosomes in the GnomAD database, including 11,415 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11415 hom., cov: 32)
• Consequence: PICALM NM_007166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PICALM	NM_007166.4	c.453-3366T>C		intron_variant		ENST00000393346.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PICALM	ENST00000393346.8	c.453-3366T>C		intron_variant		1	NM_007166.4

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58109 AN: 151910 Hom.: 11411 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.317

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.383

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.382 AC: 58138 AN: 152030 Hom.: 11415 Cov.: 32 AF XY: 0.378 AC XY: 28099 AN XY: 74320

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.386

Alfa AF: 0.357 Hom.: 14936

Bravo AF: 0.392

Asia WGS AF: 0.488 AC: 1694 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.1
Dann	Benign	0.64

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: rs642949; hg19: chr11-85729372;