Genetic Variant PICALM:c.-24+180C>A (chr11-86069540-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001206947.2(PICALM):c.-24+180C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,352 control chromosomes in the GnomAD database, including 1,449 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 0.12 ( 1448 hom., cov: 32)

Exomes 𝑓: 0.096 ( 1 hom. )

Consequence

PICALM
NM_001206947.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.658

Publications

6 publications found

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:

ENSG00000309910 (HGNC:):

ENSG00000309910 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
PICALM	NM_001206947.2 link	c.-24+180C>A	intron_variant	Intron 1 of 18	NP_001193876.1
PICALM	XM_047427660.1 link	c.-24+180C>A	intron_variant	Intron 1 of 21	XP_047283616.1
PICALM	XM_047427666.1 link	c.-24+180C>A	intron_variant	Intron 1 of 18	XP_047283622.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
PICALM	ENST00000528398.5 link	c.-24+180C>A	intron_variant	Intron 1 of 18	2	ENSP00000434884.1
PICALM	ENST00000531930.5 link	c.-56+180C>A	intron_variant	Intron 1 of 6	5	ENSP00000433303.1
ENSG00000309910	ENST00000845444.1 link	n.180+207G>T	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18096

AN:

152100

Hom.:

1448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0357

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.147

Gnomad ASJ

AF:

0.0945

Gnomad EAS

AF:

0.367

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.103

GnomAD4 exome

AF:

0.0956

AC:

AN:

136

Hom.:

Cov.:

AF XY:

0.0932

AC XY:

AN XY:

118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.125

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0814

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.119

AC:

18099

AN:

152216

Hom.:

1448

Cov.:

AF XY:

0.120

AC XY:

8919

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0356

AC:

1480

AN:

41554

American (AMR)

AF:

0.147

AC:

2254

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0945

AC:

328

AN:

3472

East Asian (EAS)

AF:

0.367

AC:

1887

AN:

5146

South Asian (SAS)

AF:

0.183

AC:

884

AN:

4820

European-Finnish (FIN)

AF:

0.121

AC:

1283

AN:

10608

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9676

AN:

67996

Other (OTH)

AF:

0.107

AC:

226

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

795

1590

2385

3180

3975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0788

Hom.:

137

Bravo

AF:

0.116

Asia WGS

AF:

0.263

AC:

913

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.30

(source)

DANN

Benign

0.49

PhyloP100

-0.66

PromoterAI

-0.012

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over