rs115892604

chr15-23646705-C-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.1038G>C(p.Arg346Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,529,866 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.386

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=0.0056635737).
• BP6: Variant 15-23646705-C-G is Benign according to our data. Variant chr15-23646705-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 211415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23646705-C-G is described in Lovd as [Benign]. Variant chr15-23646705-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00558 (849/152106) while in subpopulation AFR AF= 0.0193 (800/41490). AF 95% confidence interval is 0.0182. There are 12 homozygotes in gnomad4. There are 436 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 849 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.1038G>C	p.Arg346Ser	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.1038G>C	p.Arg346Ser	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.00559 AC: 849 AN: 151988 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00102 AC: 136 AN: 133608 Hom.: 1 AF XY: 0.000789 AC XY: 57 AN XY: 72276

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.000701

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: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000514 AC: 708 AN: 1377760 Hom.: 4 Cov.: 32 AF XY: 0.000414 AC XY: 281 AN XY: 679058

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.000877

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: 0.00000651

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00558 AC: 849 AN: 152106 Hom.: 12 Cov.: 33 AF XY: 0.00586 AC XY: 436 AN XY: 74366

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00122 Hom.: 3

Bravo AF: 0.00660

ExAC AF: 0.000932 AC: 20

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 16, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Benign	0.53
DEOGEN2	Benign	0.099	T;T
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.0057	T;T
PrimateAI	Pathogenic	0.79	T
Sift4G	Benign	0.72	T;.
Vest4		0.52
MVP		0.21
GERP RS		1.4
Varity_R		0.16
gMVP		0.13

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: rs115892604; hg19: chr15-23891852;