rs770374710

Positions:

• chr15-23645746-TG-T
• chr15-23645746-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_019066.5(MAGEL2):​c.1996del​(p.Gln666SerfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,421,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAGEL2 NM_019066.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-23645746-TG-T is Pathogenic according to our data. Variant chr15-23645746-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 440463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23645746-TG-T is described in Lovd as [Pathogenic]. Variant chr15-23645746-TG-T is described in Lovd as [Pathogenic]. Variant chr15-23645746-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEL2	NM_019066.5	c.1996del	p.Gln666SerfsTer36	frameshift_variant	1/1	ENST00000650528.1	NP_061939.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEL2	ENST00000650528.1	c.1996del	p.Gln666SerfsTer36	frameshift_variant	1/1		NM_019066.5	ENSP00000497810	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421014 Hom.: 0 Cov.: 32 AF XY: 0.00000284 AC XY: 2 AN XY: 703224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 24, 2017	A different truncation downstream of this variant (c.1996dupC) has been determined to be pathogenic (PMID: 27195816). This suggests that deletion of this region of the MAGEL2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MAGEL2 are known to be pathogenic (PMID: 27195816). This particular variant has been reported in an individual with severe arthrogryposis and fetal akinesia (PMID: 26365340). While this variant is present in population databases (rs773586710), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the last exon of the MAGEL2 mRNA at codon 666 (p.Gln666Serfs*36). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 583 amino acids of the MAGEL2 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2020	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 584 amino acids are lost and replaced with 36 incorrect amino acids; This variant is associated with the following publications: (PMID: 31680349, 31397880, 30302899, 26365340, 31152388, 27195816) -

Schaaf-Yang syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 22, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	Pre- or perinatally lethal in all reported affected persons -

Multiple joint contractures;C0266362:Ambiguous genitalia;C1858120:Generalized hypotonia;C3278923:Ventriculomegaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Reproductive Medicine, Peking University Third Hospital

Oct 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs770374710; hg19: chr15-23890893;