rs2233061

chr15-23646457-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 7/11 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.68

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 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 539 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.1286C>T	p.Pro429Leu	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.1286C>T	p.Pro429Leu	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 539 AN: 151334 Hom.: 2 Cov.: 33

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.: 3 AF XY: 0.00330 AC XY: 76 AN XY: 23038

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.: 23 Cov.: 32 AF XY: 0.00465 AC XY: 2882 AN XY: 619130

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.: 2 Cov.: 33 AF XY: 0.00328 AC XY: 243 AN XY: 74018

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.: 0

Bravo AF: 0.00417

ExAC AF: 0.00137 AC: 26

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

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

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	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.13	T;T
FATHMM_MKL	Benign	0.031	N
MetaRNN	Benign	0.0063	T;T
PrimateAI	Pathogenic	0.79	T
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

Other links and lift over

dbSNP: rs2233061; hg19: chr15-23891604;