chr15-23646457-G-A

Variant names:

• chr15-23646457-G-A
• rs2233061
• NM_019066.5:c.1286C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.68
• Publications: 1 publications found

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: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

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

Selected	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

Ensembl Transcripts

Selected	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

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 539 AN: 151334 Hom.: 2 Cov.: 33

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

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.: 23 Cov.: 32 AF XY: 0.00465 AC XY: 2882 AN XY: 619130

African (AFR) AF: 0.000642 AC: 17 AN: 26486

American (AMR) AF: 0.00294 AC: 54 AN: 18364

Ashkenazi Jewish (ASJ) AF: 0.00640 AC: 117 AN: 18280

East Asian (EAS) AF: 0.0000305 AC: 1 AN: 32744

South Asian (SAS) AF: 0.00535 AC: 330 AN: 61670

European-Finnish (FIN) AF: 0.000728 AC: 22 AN: 30226

Middle Eastern (MID) AF: 0.0120 AC: 44 AN: 3678

European-Non Finnish (NFE) AF: 0.00490 AC: 5047 AN: 1030654

Other (OTH) AF: 0.00412 AC: 218 AN: 52904

GnomAD4 genome AF: 0.00356 AC: 539 AN: 151444 Hom.: 2 Cov.: 33 AF XY: 0.00328 AC XY: 243 AN XY: 74018

African (AFR) AF: 0.000581 AC: 24 AN: 41296

American (AMR) AF: 0.00269 AC: 41 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00396 AC: 19 AN: 4802

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10568

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00505 AC: 342 AN: 67690

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00301 Hom.: 0

Bravo AF: 0.00417

ExAC AF: 0.00137 AC: 26

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0063	T
PhyloP100		1.7
PrimateAI	Pathogenic	0.79	T
Sift4G	Uncertain	0.0080	D
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

Other links and lift over

dbSNP: rs2233061; hg19: chr15-23891604;