rs2233068

Positions:

• chr15-23644857-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_019066.5(MAGEL2):​c.2886C>T​(p.Ser962=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,612,178 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (58 hom.)
• Consequence: MAGEL2 NM_019066.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.163

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-23644857-G-A is Benign according to our data. Variant chr15-23644857-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23644857-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.163 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00323 (492/152260) while in subpopulation SAS AF= 0.0199 (96/4820). AF 95% confidence interval is 0.0167. There are 3 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.2886C>T	p.Ser962=	synonymous_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.2886C>T	p.Ser962=	synonymous_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 490 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00543 AC: 1334 AN: 245862 Hom.: 18 AF XY: 0.00650 AC XY: 871 AN XY: 133930

Gnomad AFR exome AF: 0.000527

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.000336

Gnomad SAS exome AF: 0.0204

Gnomad FIN exome AF: 0.00221

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00416 AC: 6075 AN: 1459918 Hom.: 58 Cov.: 32 AF XY: 0.00478 AC XY: 3474 AN XY: 726312

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.00299

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00390 AC XY: 290 AN XY: 74444

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.000970

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00318

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00390 Hom.: 0

Bravo AF: 0.00283

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00398

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAGEL2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 30, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.4
DANN	Benign	0.72

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: rs2233068; hg19: chr15-23890004; COSMIC: COSV58567821;