dbSNP rs1250752332: MAGEL2:p.Pro13HisfsTer18 (chr15-23647705-G-GGT) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_019066.5(MAGEL2):c.37_38insAC(p.Pro13HisfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,331,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

MAGEL2
NM_019066.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.87

Publications

0 publications found

Variant links:

Genes affected

MAGEL2 (HGNC:6814): (MAGE family member L2) Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13 region. Affected individuals exhibit neonatal hypotonia, developmental delay, and childhood-onset obesity. Necdin (NDN), a gene involved in the terminal differentiation of neurons, localizes to this region of the genome and has been implicated as one of the genes responsible for the etiology of PWS. This gene is structurally similar to NDN, is also localized to the PWS chromosomal region, and is paternally imprinted, suggesting a possible role for it in PWS. [provided by RefSeq, Oct 2010]

MAGEL2 Gene-Disease associations (from GenCC):

Schaaf-Yang syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

MAGEL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 92 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEL2	NM_019066.5 link	c.37_38insAC	p.Pro13HisfsTer18	frameshift_variant	Exon 1 of 1	ENST00000650528.1	NP_061939.3	Q9UJ55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEL2	ENST00000650528.1 link	c.37_38insAC	p.Pro13HisfsTer18	frameshift_variant	Exon 1 of 1		NM_019066.5	ENSP00000497810.1		Q9UJ55

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1331740

Hom.:

Cov.:

AF XY:

0.00000306

AC XY:

AN XY:

652764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29136

American (AMR)

AF:

0.00

AC:

AN:

24202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21918

East Asian (EAS)

AF:

0.00

AC:

AN:

35092

South Asian (SAS)

AF:

0.00

AC:

AN:

71462

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5004

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1056202

Other (OTH)

AF:

0.00

AC:

AN:

55240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 17, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Aug 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Pro13Hisfs*18) in the MAGEL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1237 amino acid(s) of the MAGEL2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAGEL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 435801). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over