rs200926181

Positions:

chr15-23645669-C-T

Variant summary

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

The NM_019066.5(MAGEL2):c.2074G>A(p.Val692Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,567,664 control chromosomes in the GnomAD database, including 41 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. V692V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 36 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.387

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=0.003316313).

BP6

Variant 15-23645669-C-T is Benign according to our data. Variant chr15-23645669-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 193400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23645669-C-T is described in Lovd as [Benign]. Variant chr15-23645669-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00205 (312/152352) while in subpopulation SAS AF= 0.0193 (93/4830). AF 95% confidence interval is 0.0161. There are 5 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 312 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5 linkuse as main transcript	c.2074G>A	p.Val692Ile	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.2074G>A	p.Val692Ile	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00206

AC:

313

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0194

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00248

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00388

AC:

749

AN:

192994

Hom.:

AF XY:

0.00468

AC XY:

489

AN XY:

104490

show subpopulations

Gnomad AFR exome

AF:

0.000637

Gnomad AMR exome

AF:

0.000992

Gnomad ASJ exome

AF:

0.00389

Gnomad EAS exome

AF:

0.000191

Gnomad SAS exome

AF:

0.0210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00266

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00332

AC:

4700

AN:

1415312

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

2662

AN XY:

699806

show subpopulations

Gnomad4 AFR exome

AF:

0.000531

Gnomad4 AMR exome

AF:

0.00106

Gnomad4 ASJ exome

AF:

0.00365

Gnomad4 EAS exome

AF:

0.000128

Gnomad4 SAS exome

AF:

0.0201

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.00248

Gnomad4 OTH exome

AF:

0.00392

GnomAD4 genome

AF:

0.00205

AC:

312

AN:

152352

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0193

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00248

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000268

AC:

ESP6500EA

AF:

0.00159

AC:

ExAC

AF:

0.00359

AC:

432

Asia WGS

AF:

0.00636

AC:

AN:

3476

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 07, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Prader-Willi syndrome;C5575066:Schaaf-Yang syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.6

DANN

Benign

0.96

DEOGEN2

Benign

0.046

T;T

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.44

.;T

MetaRNN

Benign

0.0033

T;T

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

Sift4G

Uncertain

0.043

D;.

Vest4

0.043

MVP

0.043

MPC

0.054

GERP RS

1.4

Varity_R

0.015

gMVP

0.11

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