Genetic Variant NM_019066.5:c.1286C>T (chr15-23646457-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_019066.5(MAGEL2):c.1286C>T(p.Pro429Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,426,450 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 23 hom. )

Consequence

MAGEL2
NM_019066.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.68

Publications

1 publications found

Variant links:

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]

MAGEL2 Gene-Disease associations (from GenCC):

Schaaf-Yang syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Illumina

MAGEL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063458383).

BP6

Variant 15-23646457-G-A is Benign according to our data. Variant chr15-23646457-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193401.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00356 (539/151444) while in subpopulation NFE AF = 0.00505 (342/67690). AF 95% confidence interval is 0.00461. There are 2 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 539 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019066.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEL2	NM_019066.5	MANE Select	c.1286C>T	p.Pro429Leu	missense	Exon 1 of 1	NP_061939.3	Q9UJ55

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEL2	ENST00000650528.1	MANE Select	c.1286C>T	p.Pro429Leu	missense	Exon 1 of 1	ENSP00000497810.1	Q9UJ55

Frequencies

GnomAD3 genomes

AF:

0.00356

AC:

539

AN:

151334

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000583

Gnomad AMI

AF:

0.0837

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00395

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00505

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00331

AC:

152

AN:

45914

AF XY:

0.00330

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00758

Gnomad EAS exome

AF:

0.000173

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00511

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00459

AC:

5850

AN:

1275006

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

2882

AN XY:

619130

show subpopulations

African (AFR)

AF:

0.000642

AC:

AN:

26486

American (AMR)

AF:

0.00294

AC:

AN:

18364

Ashkenazi Jewish (ASJ)

AF:

0.00640

AC:

117

AN:

18280

East Asian (EAS)

AF:

0.0000305

AC:

AN:

32744

South Asian (SAS)

AF:

0.00535

AC:

330

AN:

61670

European-Finnish (FIN)

AF:

0.000728

AC:

AN:

30226

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

3678

European-Non Finnish (NFE)

AF:

0.00490

AC:

5047

AN:

1030654

Other (OTH)

AF:

0.00412

AC:

218

AN:

52904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

406

812

1219

1625

2031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00356

AC:

539

AN:

151444

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

243

AN XY:

74018

show subpopulations

African (AFR)

AF:

0.000581

AC:

AN:

41296

American (AMR)

AF:

0.00269

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5070

South Asian (SAS)

AF:

0.00396

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.000473

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00505

AC:

342

AN:

67690

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.00417

ExAC

AF:

0.00137

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0063

PhyloP100

1.7

PrimateAI

Pathogenic

0.79

Sift4G

Uncertain

0.0080

Vest4

0.23

MVP

0.043

GERP RS

2.3

Varity_R

0.090

gMVP

0.12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over