rs188762916

Variant names:

• chr15-23647358-T-C
• rs188762916
• NM_019066.5:c.385A>G

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.385A>G​(p.Met129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,536,668 control chromosomes in the GnomAD database, including 1 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 0.0011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: MAGEL2 NM_019066.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.00
• Publications: 4 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=0.023264885).
• BP6: Variant 15-23647358-T-C is Benign according to our data. Variant chr15-23647358-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435800.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0011 (167/151964) while in subpopulation AMR AF = 0.00248 (38/15304). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 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.385A>G	p.Met129Val	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.385A>G	p.Met129Val	missense	Exon 1 of 1	ENSP00000497810.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 151846 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000995 AC: 140 AN: 140676 AF XY: 0.000941

Gnomad AFR exome AF: 0.000275

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.0000943

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000951

GnomAD4 exome AF: 0.00137 AC: 1896 AN: 1384704 Hom.: 1 Cov.: 32 AF XY: 0.00127 AC XY: 867 AN XY: 683288

African (AFR) AF: 0.000317 AC: 10 AN: 31582

American (AMR) AF: 0.00154 AC: 55 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.000278 AC: 7 AN: 25170

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.000265 AC: 21 AN: 79232

European-Finnish (FIN) AF: 0.000516 AC: 18 AN: 34852

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5686

European-Non Finnish (NFE) AF: 0.00158 AC: 1706 AN: 1078856

Other (OTH) AF: 0.00123 AC: 71 AN: 57904

GnomAD4 genome AF: 0.00110 AC: 167 AN: 151964 Hom.: 0 Cov.: 34 AF XY: 0.000996 AC XY: 74 AN XY: 74288

African (AFR) AF: 0.000193 AC: 8 AN: 41460

American (AMR) AF: 0.00248 AC: 38 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 67888

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000660 AC: 15

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	Prader-Willi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.37
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.023	T
PhyloP100		1.0
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.31	T
Vest4		0.54
MVP		0.068
GERP RS		-2.7
Varity_R		0.25
gMVP		0.20

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: rs188762916; hg19: chr15-23892505;