Genetic Variant PICALM:p.Gln174His (chr11-86014894-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007166.4(PICALM):c.522G>C(p.Gln174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q174Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PICALM
NM_007166.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.238

Publications

43 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PICALM	NM_007166.4	MANE Select	c.522G>C	p.Gln174His	missense	Exon 5 of 20	NP_009097.2	Q13492-1
PICALM	NM_001206946.2		c.522G>C	p.Gln174His	missense	Exon 5 of 20	NP_001193875.1	Q13492-5
PICALM	NM_001411034.1		c.522G>C	p.Gln174His	missense	Exon 5 of 19	NP_001397963.1	Q13492-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PICALM	ENST00000393346.8	TSL:1 MANE Select	c.522G>C	p.Gln174His	missense	Exon 5 of 20	ENSP00000377015.3	Q13492-1
PICALM	ENST00000526033.5	TSL:1	c.522G>C	p.Gln174His	missense	Exon 5 of 20	ENSP00000433846.1	Q13492-5
PICALM	ENST00000532317.5	TSL:1	c.522G>C	p.Gln174His	missense	Exon 5 of 20	ENSP00000436958.1	Q13492-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1422018

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709148

African (AFR)

AF:

0.00

AC:

AN:

32134

American (AMR)

AF:

0.00

AC:

AN:

42760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25754

East Asian (EAS)

AF:

0.00

AC:

AN:

38758

South Asian (SAS)

AF:

0.00

AC:

AN:

83592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081570

Other (OTH)

AF:

0.00

AC:

AN:

58956

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.066

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.6

PhyloP100

0.24

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MutPred

0.81

Loss of stability (P = 0.2144)

MVP

0.91

MPC

1.1

ClinPred

1.0

GERP RS

-1.5

Varity_R

0.92

gMVP

0.87

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over