rs2233061

Positions:

chr15-23646457-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_019066.5(MAGEL2):c.1286C>T(p.Pro429Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,426,450 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 23 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.68

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063458383).

BP6

Variant 15-23646457-G-A is Benign according to our data. Variant chr15-23646457-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193401.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr15-23646457-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00356 (539/151444) while in subpopulation NFE AF= 0.00505 (342/67690). AF 95% confidence interval is 0.00461. There are 2 homozygotes in gnomad4. There are 243 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 539 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEL2	NM_019066.5 linkuse as main transcript	c.1286C>T	p.Pro429Leu	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.1286C>T	p.Pro429Leu	missense_variant	1/1		NM_019066.5	ENSP00000497810	P1

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

539

AN:

151334

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000583

Gnomad AMI

AF:

0.0837

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00395

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00505

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00331

AC:

152

AN:

45914

Hom.:

AF XY:

0.00330

AC XY:

AN XY:

23038

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00758

Gnomad EAS exome

AF:

0.000173

Gnomad SAS exome

AF:

0.00354

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00511

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00459

AC:

5850

AN:

1275006

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

2882

AN XY:

619130

show subpopulations

Gnomad4 AFR exome

AF:

0.000642

Gnomad4 AMR exome

AF:

0.00294

Gnomad4 ASJ exome

AF:

0.00640

Gnomad4 EAS exome

AF:

0.0000305

Gnomad4 SAS exome

AF:

0.00535

Gnomad4 FIN exome

AF:

0.000728

Gnomad4 NFE exome

AF:

0.00490

Gnomad4 OTH exome

AF:

0.00412

GnomAD4 genome

AF:

0.00356

AC:

539

AN:

151444

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

243

AN XY:

74018

show subpopulations

Gnomad4 AFR

AF:

0.000581

Gnomad4 AMR

AF:

0.00269

Gnomad4 ASJ

AF:

0.00635

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00396

Gnomad4 FIN

AF:

0.000473

Gnomad4 NFE

AF:

0.00505

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.00417

ExAC

AF:

0.00137

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAGEL2: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 27, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.13

T;T

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.56

.;T

MetaRNN

Benign

0.0063

T;T

PrimateAI

Pathogenic

0.79

Sift4G

Uncertain

0.0080

D;.

Vest4

0.23

MVP

0.043

GERP RS

2.3

Varity_R

0.090

gMVP

0.12

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