rs188762916

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_019066.5(MAGEL2):c.385A>G(p.Met129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,536,668 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.00

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023264885).

BP6

Variant 15-23647358-T-C is Benign according to our data. Variant chr15-23647358-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435800.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0011 (167/151964) while in subpopulation AMR AF = 0.00248 (38/15304). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 167 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEL2	NM_019066.5 link	c.385A>G	p.Met129Val	missense_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.385A>G	p.Met129Val	missense_variant	Exon 1 of 1		NM_019066.5	ENSP00000497810.1		Q9UJ55

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000995

AC:

140

AN:

140676

AF XY:

0.000941

show subpopulations

Gnomad AFR exome

AF:

0.000275

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.0000943

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.000951

GnomAD4 exome

AF:

0.00137

AC:

1896

AN:

1384704

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

867

AN XY:

683288

show subpopulations

African (AFR)

AF:

0.000317

AC:

AN:

31582

American (AMR)

AF:

0.00154

AC:

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.000278

AC:

AN:

25170

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35734

South Asian (SAS)

AF:

0.000265

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.000516

AC:

AN:

34852

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00158

AC:

1706

AN:

1078856

Other (OTH)

AF:

0.00123

AC:

AN:

57904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

135

270

404

539

674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

151964

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41460

American (AMR)

AF:

0.00248

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.000415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00162

AC:

110

AN:

67888

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000660

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 06, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAGEL2: BS1 -

not specified

Uncertain:1

Oct 13, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 26, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Prader-Willi syndrome

Benign:1

Oct 04, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.16

T;T

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.51

.;T

MetaRNN

Benign

0.023

T;T

PhyloP100

1.0

PrimateAI

Pathogenic

0.80

Sift4G

Benign

0.31

T;.

Vest4

0.54

MVP

0.068

GERP RS

-2.7

Varity_R

0.25

gMVP

0.20

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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rs188762916

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over