chr15-23644726-G-C

Position:

chr15-23644726-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019066.5(MAGEL2):c.3017C>G(p.Thr1006Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,613,800 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 21 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.419

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=0.0063773096).

BP6

Variant 15-23644726-G-C is Benign according to our data. Variant chr15-23644726-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 193399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23644726-G-C is described in Lovd as [Benign]. Variant chr15-23644726-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00338 (514/152244) while in subpopulation NFE AF= 0.0059 (401/68014). AF 95% confidence interval is 0.00542. There are 2 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 514 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5 linkuse as main transcript	c.3017C>G	p.Thr1006Ser	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1 linkuse as main transcript	c.3017C>G	p.Thr1006Ser	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

514

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00590

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00334

AC:

832

AN:

249152

Hom.:

AF XY:

0.00320

AC XY:

433

AN XY:

135188

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00580

Gnomad NFE exome

AF:

0.00538

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00466

AC:

6817

AN:

1461556

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

3287

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00590

Gnomad4 NFE exome

AF:

0.00553

Gnomad4 OTH exome

AF:

0.00356

GnomAD4 genome

AF:

0.00338

AC:

514

AN:

152244

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.00590

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00425

Hom.:

Bravo

AF:

0.00291

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000748

AC:

ESP6500EA

AF:

0.00562

AC:

ExAC

AF:

0.00331

AC:

400

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MAGEL2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Prader-Willi syndrome;C5575066:Schaaf-Yang syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.1

DANN

Benign

0.53

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

M_CAP

Benign

0.0078

MetaRNN

Benign

0.0064

T;T

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

Sift4G

Benign

0.35

T;.

Vest4

0.022

MVP

0.043

MPC

0.059

ClinPred

0.00040

GERP RS

-1.8

Varity_R

0.028

gMVP

0.14

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