rs201984254

chr15-23645453-C-T

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.2290G>A(p.Ala764Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,613,978 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict 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. A764V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.09

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=0.004958838).
• BP6: Variant 15-23645453-C-T is Benign according to our data. Variant chr15-23645453-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23645453-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000735 (112/152358) while in subpopulation AMR AF= 0.00222 (34/15308). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.2290G>A	p.Ala764Thr	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.2290G>A	p.Ala764Thr	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

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: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000735 AC: 183 AN: 248860 Hom.: 0 AF XY: 0.000659 AC XY: 89 AN XY: 135088

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00113 AC: 1652 AN: 1461620 Hom.: 4 Cov.: 32 AF XY: 0.00109 AC XY: 796 AN XY: 727094

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000684 AC XY: 51 AN XY: 74516

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000975

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.00108 AC: 9

ExAC AF: 0.000629 AC: 76

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MAGEL2: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.1
Dann	Benign	0.89
DEOGEN2	Benign	0.069	T;T
FATHMM_MKL	Benign	0.32	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0050	T;T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.53	T;.
Vest4		0.036
MVP		0.043
MPC		0.067
GERP RS		-4.4
Varity_R		0.018
gMVP		0.23

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: rs201984254; hg19: chr15-23890600;