rs180690391

Positions:

• chr15-23645051-T-C

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.2692A>G​(p.Ser898Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,613,948 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.410

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=0.0027456582).
• BP6: Variant 15-23645051-T-C is Benign according to our data. Variant chr15-23645051-T-C is described in ClinVar as [Benign]. Clinvar id is 445351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23645051-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0052 (792/152372) while in subpopulation AFR AF= 0.0187 (776/41600). AF 95% confidence interval is 0.0176. There are 7 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 792 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEL2	NM_019066.5	c.2692A>G	p.Ser898Gly	missense_variant	1/1	ENST00000650528.1	NP_061939.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEL2	ENST00000650528.1	c.2692A>G	p.Ser898Gly	missense_variant	1/1		NM_019066.5	ENSP00000497810	P1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152254 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00126 AC: 313 AN: 249324 Hom.: 3 AF XY: 0.00102 AC XY: 138 AN XY: 135228

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00101

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: 0.00000885

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000492 AC: 719 AN: 1461576 Hom.: 4 Cov.: 32 AF XY: 0.000458 AC XY: 333 AN XY: 727082

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00520 AC: 792 AN: 152372 Hom.: 7 Cov.: 32 AF XY: 0.00484 AC XY: 361 AN XY: 74516

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00108 Hom.: 2

Bravo AF: 0.00557

ESP6500AA AF: 0.0138 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.0
DANN	Benign	0.49
DEOGEN2	Benign	0.051	T;T
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.26	.;T
MetaRNN	Benign	0.0027	T;T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.42	T;.
Vest4		0.036
MVP		0.043
MPC		0.060
GERP RS		-1.3
Varity_R		0.030
gMVP		0.048

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: rs180690391; hg19: chr15-23890198;