rs74004212

chr15-23645131-G-A

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.2612C>T(p.Ala871Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,613,784 control chromosomes in the GnomAD database, including 36 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A871F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (17 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.683

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=0.002413839).
• BP6: Variant 15-23645131-G-A is Benign according to our data. Variant chr15-23645131-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-23645131-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00905 (1379/152372) while in subpopulation AFR AF= 0.0317 (1318/41590). AF 95% confidence interval is 0.0303. There are 19 homozygotes in gnomad4. There are 644 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEL2	NM_019066.5	c.2612C>T	p.Ala871Val	missense_variant	1/1	ENST00000650528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEL2	ENST00000650528.1	c.2612C>T	p.Ala871Val	missense_variant	1/1		NM_019066.5	P1

Frequencies

GnomAD3 genomes AF: 0.00904 AC: 1376 AN: 152256 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00216 AC: 537 AN: 248946 Hom.: 4 AF XY: 0.00166 AC XY: 225 AN XY: 135170

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000927 AC: 1354 AN: 1461412 Hom.: 17 Cov.: 32 AF XY: 0.000780 AC XY: 567 AN XY: 727002

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00905 AC: 1379 AN: 152372 Hom.: 19 Cov.: 32 AF XY: 0.00864 AC XY: 644 AN XY: 74520

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00181 Hom.: 4

Bravo AF: 0.00992

ESP6500AA AF: 0.0292 AC: 127

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely 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	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 08, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.31	N
MetaRNN	Benign	0.0024	T;T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.038	D;.
Vest4		0.044
MVP		0.043
MPC		0.067
ClinPred		0.00023	T
GERP RS		1.2
Varity_R		0.039
gMVP		0.16

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: rs74004212; hg19: chr15-23890278;