rs4944550

Variant names:

• chr11-85974531-C-T
• rs4944550
• NM_007166.4:c.1944+177G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007166.4(PICALM):​c.1944+177G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 709,054 control chromosomes in the GnomAD database, including 12,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2497 hom., cov: 32)
  • Exomes 𝑓: 0.17 (10139 hom.)
• Consequence: PICALM NM_007166.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.201
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 11-85974531-C-T is Benign according to our data. Variant chr11-85974531-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 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.1944+177G>A		intron	N/A	NP_009097.2	Q13492-1
	PICALM	NM_001206946.2		c.1923+177G>A		intron	N/A	NP_001193875.1	Q13492-5
	PICALM	NM_001411034.1		c.1884+177G>A		intron	N/A	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.1944+177G>A		intron	N/A	ENSP00000377015.3	Q13492-1
	PICALM	ENST00000526033.5	TSL:1	c.1923+177G>A		intron	N/A	ENSP00000433846.1	Q13492-5
	PICALM	ENST00000532317.5	TSL:1	c.1818+177G>A		intron	N/A	ENSP00000436958.1	Q13492-3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24204 AN: 152072 Hom.: 2496 Cov.: 32

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0655

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.173 AC: 96510 AN: 556862 Hom.: 10139 Cov.: 4 AF XY: 0.170 AC XY: 51732 AN XY: 305070

African (AFR) AF: 0.0637 AC: 1019 AN: 15992

American (AMR) AF: 0.0962 AC: 3864 AN: 40170

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 4616 AN: 19120

East Asian (EAS) AF: 0.000395 AC: 13 AN: 32936

South Asian (SAS) AF: 0.0749 AC: 4995 AN: 66694

European-Finnish (FIN) AF: 0.287 AC: 9878 AN: 34394

Middle Eastern (MID) AF: 0.187 AC: 714 AN: 3822

European-Non Finnish (NFE) AF: 0.211 AC: 66162 AN: 314224

Other (OTH) AF: 0.178 AC: 5249 AN: 29510

GnomAD4 genome AF: 0.159 AC: 24193 AN: 152192 Hom.: 2497 Cov.: 32 AF XY: 0.160 AC XY: 11913 AN XY: 74412

African (AFR) AF: 0.0675 AC: 2804 AN: 41540

American (AMR) AF: 0.135 AC: 2070 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4820

European-Finnish (FIN) AF: 0.313 AC: 3307 AN: 10570

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14230 AN: 67998

Other (OTH) AF: 0.180 AC: 380 AN: 2114

Alfa AF: 0.164 Hom.: 840

Bravo AF: 0.144

Asia WGS AF: 0.0440 AC: 155 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.61
PhyloP100		0.20
Mutation Taster		=100/0	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: rs4944550; hg19: chr11-85685574;