NM_007166.4:c.1770T>G

Variant names:

• chr11-85981138-A-C
• rs694353
• NM_007166.4:c.1770T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_007166.4(PICALM):​c.1770T>G​(p.Ala590Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 1,539,134 control chromosomes in the GnomAD database, including 266,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A590A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.59 (26907 hom., cov: 33)
  • Exomes 𝑓: 0.58 (239128 hom.)
• Consequence: PICALM NM_007166.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.37
• Publications: 18 publications found

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.034).
• BP6: Variant 11-85981138-A-C is Benign according to our data. Variant chr11-85981138-A-C is described in ClinVar as Benign. ClinVar VariationId is 403297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PICALM	NM_007166.4	MANE Select	c.1770T>G	p.Ala590Ala	synonymous	Exon 17 of 20	NP_009097.2	Q13492-1
	PICALM	NM_001206946.2		c.1749T>G	p.Ala583Ala	synonymous	Exon 17 of 20	NP_001193875.1	Q13492-5
	PICALM	NM_001411034.1		c.1770T>G	p.Ala590Ala	synonymous	Exon 17 of 19	NP_001397963.1	Q13492-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PICALM	ENST00000393346.8	TSL:1 MANE Select	c.1770T>G	p.Ala590Ala	synonymous	Exon 17 of 20	ENSP00000377015.3	Q13492-1
	PICALM	ENST00000526033.5	TSL:1	c.1749T>G	p.Ala583Ala	synonymous	Exon 17 of 20	ENSP00000433846.1	Q13492-5
	PICALM	ENST00000532317.5	TSL:1	c.1620T>G	p.Ala540Ala	synonymous	Exon 16 of 20	ENSP00000436958.1	Q13492-3

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90083 AN: 151998 Hom.: 26886 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.597 AC: 149489 AN: 250604 AF XY: 0.597

Gnomad AFR exome AF: 0.613

Gnomad AMR exome AF: 0.644

Gnomad ASJ exome AF: 0.491

Gnomad EAS exome AF: 0.661

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.599

GnomAD4 exome AF: 0.584 AC: 810694 AN: 1387018 Hom.: 239128 Cov.: 23 AF XY: 0.587 AC XY: 407591 AN XY: 694432

African (AFR) AF: 0.615 AC: 19527 AN: 31748

American (AMR) AF: 0.638 AC: 28329 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 12636 AN: 25682

East Asian (EAS) AF: 0.667 AC: 26180 AN: 39268

South Asian (SAS) AF: 0.650 AC: 54871 AN: 84466

European-Finnish (FIN) AF: 0.510 AC: 27219 AN: 53320

Middle Eastern (MID) AF: 0.555 AC: 3117 AN: 5612

European-Non Finnish (NFE) AF: 0.579 AC: 604717 AN: 1044662

Other (OTH) AF: 0.589 AC: 34098 AN: 57856

GnomAD4 genome AF: 0.593 AC: 90155 AN: 152116 Hom.: 26907 Cov.: 33 AF XY: 0.588 AC XY: 43744 AN XY: 74360

African (AFR) AF: 0.611 AC: 25356 AN: 41474

American (AMR) AF: 0.623 AC: 9527 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1705 AN: 3466

East Asian (EAS) AF: 0.660 AC: 3416 AN: 5178

South Asian (SAS) AF: 0.663 AC: 3198 AN: 4824

European-Finnish (FIN) AF: 0.488 AC: 5171 AN: 10588

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.588 AC: 39985 AN: 67974

Other (OTH) AF: 0.566 AC: 1196 AN: 2114

Alfa AF: 0.574 Hom.: 13934

Bravo AF: 0.599

EpiCase AF: 0.585

EpiControl AF: 0.580

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	PICALM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs694353; hg19: chr11-85692181; COSMIC: COSV62671300; COSMIC: COSV62671300;