rs111759069

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019066.5(MAGEL2):c.1079C>T(p.Ala360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0098 in 1,504,542 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A360A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0069 ( 7 hom., cov: 33)

Exomes 𝑓: 0.010 ( 107 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.469

Publications

3 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=0.0054139197).

BP6

Variant 15-23646664-G-A is Benign according to our data. Variant chr15-23646664-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00691 (1052/152188) while in subpopulation NFE AF = 0.0125 (850/67982). AF 95% confidence interval is 0.0118. There are 7 homozygotes in GnomAd4. There are 453 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1052 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEL2	NM_019066.5 link	c.1079C>T	p.Ala360Val	missense_variant	Exon 1 of 1	ENST00000650528.1	NP_061939.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEL2	ENST00000650528.1 link	c.1079C>T	p.Ala360Val	missense_variant	Exon 1 of 1		NM_019066.5	ENSP00000497810.1

Frequencies

GnomAD3 genomes

AF:

0.00692

AC:

1053

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0125

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00570

AC:

642

AN:

112578

AF XY:

0.00581

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.000176

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00467

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00496

GnomAD4 exome

AF:

0.0101

AC:

13691

AN:

1352354

Hom.:

107

Cov.:

AF XY:

0.00986

AC XY:

6540

AN XY:

663390

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

30892

American (AMR)

AF:

0.00152

AC:

AN:

32998

Ashkenazi Jewish (ASJ)

AF:

0.000220

AC:

AN:

22694

East Asian (EAS)

AF:

0.00

AC:

AN:

35458

South Asian (SAS)

AF:

0.000355

AC:

AN:

73342

European-Finnish (FIN)

AF:

0.00446

AC:

145

AN:

32508

Middle Eastern (MID)

AF:

0.000728

AC:

AN:

5492

European-Non Finnish (NFE)

AF:

0.0123

AC:

13033

AN:

1062498

Other (OTH)

AF:

0.00659

AC:

372

AN:

56472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

905

1809

2714

3618

4523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.00691

AC:

1052

AN:

152188

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

453

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41532

American (AMR)

AF:

0.00189

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0125

AC:

850

AN:

67982

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00484

Hom.:

Bravo

AF:

0.00663

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0130

AC:

ExAC

AF:

0.00128

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAGEL2: BS1, BS2 -

May 19, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jul 29, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 13, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.038

T;T

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.48

.;T

MetaRNN

Benign

0.0054

T;T

PhyloP100

0.47

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

N;.

Sift

Uncertain

0.019

D;.

Sift4G

Benign

0.32

T;.

Vest4

0.12

MVP

0.14

GERP RS

2.1

Varity_R

0.030

gMVP

0.058

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