rs191559595

chr15-23647360-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019066.5(MAGEL2):c.383T>C(p.Leu128Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,534,806 control chromosomes in the GnomAD database, including 21 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (13 hom., cov: 34)
  • Exomes 𝑓: 0.00071 (8 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052521825).
• BP6: Variant 15-23647360-A-G is Benign according to our data. Variant chr15-23647360-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00767 (1151/150162) while in subpopulation AFR AF= 0.0271 (1103/40696). AF 95% confidence interval is 0.0258. There are 13 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 1149 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.383T>C	p.Leu128Pro	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.383T>C	p.Leu128Pro	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1149 AN: 150048 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000593

Gnomad OTH AF: 0.00725

GnomAD3 exomes AF: 0.00162 AC: 228 AN: 140536 Hom.: 1 AF XY: 0.00122 AC XY: 92 AN XY: 75430

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.000652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000348

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000706 AC: 978 AN: 1384644 Hom.: 8 Cov.: 32 AF XY: 0.000591 AC XY: 404 AN XY: 683246

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.000813

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00767 AC: 1151 AN: 150162 Hom.: 13 Cov.: 34 AF XY: 0.00716 AC XY: 525 AN XY: 73368

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000593

Gnomad4 OTH AF: 0.00718

Alfa AF: 0.00440 Hom.: 3

Bravo AF: 0.00850

ExAC AF: 0.00222 AC: 50

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Benign	0.58
DEOGEN2	Benign	0.15	T;T
FATHMM_MKL	Benign	0.10	N
MetaRNN	Benign	0.0053	T;T
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.27	T;.
Vest4		0.52
MVP		0.043
GERP RS		2.6
Varity_R		0.26
gMVP		0.091

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: rs191559595; hg19: chr15-23892507;