rs111759069

Positions:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 193398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23646664-G-A is described in Lovd as [Benign]. Variant chr15-23646664-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1052 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEL2	NM_019066.5 linkuse as main transcript	c.1079C>T	p.Ala360Val	missense_variant	1/1	ENST00000650528.1	NP_061939.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEL2	ENST00000650528.1 linkuse as main transcript	c.1079C>T	p.Ala360Val	missense_variant	1/1		NM_019066.5	ENSP00000497810	P1

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

GnomAD3 exomes

AF:

0.00570

AC:

642

AN:

112578

Hom.:

AF XY:

0.00581

AC XY:

346

AN XY:

59508

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 SAS exome

AF:

0.000239

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

Gnomad4 AFR exome

AF:

0.00181

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.000220

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000355

Gnomad4 FIN exome

AF:

0.00446

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.00659

GnomAD4 genome

AF:

0.00691

AC:

1052

AN:

152188

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

453

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.0125

Gnomad4 OTH

AF:

0.00331

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAGEL2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over