chrX-54809737-A-G

Position:

chrX-54809737-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000375068.6(MAGED2):c.61A>G(p.Lys21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,087,466 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000028 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

MAGED2
ENST00000375068.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Variant links:

Genes affected

MAGED2 (HGNC:16353): (MAGE family member D2) This gene is a member of the MAGED gene family. The MAGED genes are clustered on chromosome Xp11. This gene is located in Xp11.2, a hot spot for X-linked intellectual disability (XLID). Mutations in this gene cause a form of transient antenatal Bartter's syndrome. This gene may also be involved in several types of cancer, including breast cancer and melanoma. The protein encoded by this gene is progressively recruited from the cytoplasm to the nucleoplasm during the interphase and after nucleolar stress and is thus thought to play a role in cell cycle regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

MAGED2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05163142).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAGED2	NM_177433.3 linkuse as main transcript	c.61A>G	p.Lys21Glu	missense_variant	3/13	ENST00000375068.6	NP_803182.1
MAGED2	NM_014599.6 linkuse as main transcript	c.61A>G	p.Lys21Glu	missense_variant	3/13		NP_055414.2
MAGED2	NM_201222.3 linkuse as main transcript	c.61A>G	p.Lys21Glu	missense_variant	3/13		NP_957516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6 linkuse as main transcript	c.61A>G	p.Lys21Glu	missense_variant	3/13	1	NM_177433.3	ENSP00000364209	P1	Q9UNF1-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111523

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33689

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000586

AC:

AN:

170701

Hom.:

AF XY:

0.0000176

AC XY:

AN XY:

56753

show subpopulations

Gnomad AFR exome

AF:

0.0000787

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1087466

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

355220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000772

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000120

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111523

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33689

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 21 of the MAGED2 protein (p.Lys21Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MAGED2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1985219). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;T;T;T;T;T;T;T

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.62

.;T;.;T;T;.;.;.

M_CAP

Benign

0.0095

MetaRNN

Benign

0.052

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.42

N;.;N;.;N;N;.;N

MutationTaster

Benign

1.0

D;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.41

N;.;N;.;N;N;N;N

REVEL

Benign

0.018

Sift

Benign

0.69

T;.;T;.;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.0020

B;B;B;.;B;B;B;B

Vest4

0.071

MutPred

0.15

Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);Loss of ubiquitination at K21 (P = 0.0022);

MVP

0.47

MPC

0.85

ClinPred

0.020

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over