rs180690391

Variant names:

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.2692A>G(p.Ser898Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,613,948 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S898I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 4 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.410

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:

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=0.0027456582).

BP6

Variant 15-23645051-T-C is Benign according to our data. Variant chr15-23645051-T-C is described in ClinVar as [Benign]. Clinvar id is 445351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0052 (792/152372) while in subpopulation AFR AF = 0.0187 (776/41600). AF 95% confidence interval is 0.0176. There are 7 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 792 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEL2	NM_019066.5 link	c.2692A>G	p.Ser898Gly	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.2692A>G	p.Ser898Gly	missense_variant	Exon 1 of 1		NM_019066.5	ENSP00000497810.1		Q9UJ55

Frequencies

GnomAD3 genomes

AF:

0.00516

AC:

785

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00126

AC:

313

AN:

249324

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.000492

AC:

719

AN:

1461576

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0178

AC:

597

AN:

33480

American (AMR)

AF:

0.00105

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111868

Other (OTH)

AF:

0.00104

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00520

AC:

792

AN:

152372

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

361

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0187

AC:

776

AN:

41600

American (AMR)

AF:

0.000849

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00557

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00156

AC:

189

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 24, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Aug 07, 2018

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

0.075

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.0

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.051

T;T

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.26

.;T

MetaRNN

Benign

0.0027

T;T

PhyloP100

-0.41

PrimateAI

Benign

0.25

Sift4G

Benign

0.42

T;.

Vest4

0.036

MVP

0.043

MPC

0.060

GERP RS

-1.3

Varity_R

0.030

gMVP

0.048

Mutation Taster

=99/1

polymorphism

(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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rs180690391

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