NM_019066.5:c.3151C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019066.5(MAGEL2):c.3151C>A(p.Leu1051Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 1,613,880 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 135 hom., cov: 32)

Exomes 𝑓: 0.023 ( 626 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.122

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024078488).

BP6

Variant 15-23644592-G-T is Benign according to our data. Variant chr15-23644592-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 158812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23644592-G-T is described in CliVar as Benign/Likely_benign. Clinvar id is 158812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEL2	NM_019066.5 link	c.3151C>A	p.Leu1051Ile	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.3151C>A	p.Leu1051Ile	missense_variant	Exon 1 of 1		NM_019066.5	ENSP00000497810.1		Q9UJ55

Frequencies

GnomAD3 genomes

AF:

0.0355

AC:

5399

AN:

152108

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0592

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.0479

Gnomad SAS

AF:

0.0413

Gnomad FIN

AF:

0.0599

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0411

GnomAD2 exomes

AF:

0.0312

AC:

7771

AN:

249212

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.0610

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0348

Gnomad EAS exome

AF:

0.0484

Gnomad FIN exome

AF:

0.0592

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0339

GnomAD4 exome

AF:

0.0227

AC:

33142

AN:

1461654

Hom.:

626

Cov.:

AF XY:

0.0235

AC XY:

17069

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0681

AC:

2279

AN:

33480

American (AMR)

AF:

0.0136

AC:

609

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

865

AN:

26136

East Asian (EAS)

AF:

0.0425

AC:

1686

AN:

39700

South Asian (SAS)

AF:

0.0387

AC:

3341

AN:

86258

European-Finnish (FIN)

AF:

0.0600

AC:

3201

AN:

53364

Middle Eastern (MID)

AF:

0.0484

AC:

279

AN:

5768

European-Non Finnish (NFE)

AF:

0.0171

AC:

19054

AN:

1111852

Other (OTH)

AF:

0.0303

AC:

1828

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2115

4229

6344

8458

10573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<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

AF:

0.0356

AC:

5421

AN:

152226

Hom.:

135

Cov.:

AF XY:

0.0374

AC XY:

2786

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0596

AC:

2475

AN:

41520

American (AMR)

AF:

0.0165

AC:

252

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3470

East Asian (EAS)

AF:

0.0478

AC:

247

AN:

5170

South Asian (SAS)

AF:

0.0415

AC:

200

AN:

4818

European-Finnish (FIN)

AF:

0.0599

AC:

636

AN:

10614

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0206

AC:

1404

AN:

68016

Other (OTH)

AF:

0.0417

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

266

532

798

1064

1330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0262

Hom.:

184

Bravo

AF:

0.0328

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.0539

AC:

214

ESP6500EA

AF:

0.0212

AC:

177

ExAC

AF:

0.0323

AC:

3900

Asia WGS

AF:

0.0610

AC:

212

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 18, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.7

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.035

T;T

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.068

.;T

MetaRNN

Benign

0.0024

T;T

PhyloP100

0.12

PrimateAI

Uncertain

0.60

Sift4G

Benign

1.0

T;.

Vest4

0.039

MPC

0.069

GERP RS

3.5

Varity_R

0.047

gMVP

0.14

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over