chrX-54809804-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_177433.3(MAGED2):c.128C>T(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,201,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00024 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 9 hem. )

Consequence

MAGED2
NM_177433.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.186

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Bartter disease type 5
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
antenatal Bartter syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MAGED2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028511912).

BP6

Variant X-54809804-C-T is Benign according to our data. Variant chrX-54809804-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3122179.

BS2

High Hemizygotes in GnomAd4 at 5 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177433.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGED2	NM_177433.3	MANE Select	c.128C>T	p.Pro43Leu	missense	Exon 3 of 13	NP_803182.1	Q9UNF1-1
MAGED2	NM_014599.6		c.128C>T	p.Pro43Leu	missense	Exon 3 of 13	NP_055414.2
MAGED2	NM_201222.3		c.128C>T	p.Pro43Leu	missense	Exon 3 of 13	NP_957516.1	Q9UNF1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGED2	ENST00000375068.6	TSL:1 MANE Select	c.128C>T	p.Pro43Leu	missense	Exon 3 of 13	ENSP00000364209.1	Q9UNF1-1
MAGED2	ENST00000375053.6	TSL:1	c.128C>T	p.Pro43Leu	missense	Exon 3 of 12	ENSP00000364193.2	Q9UNF1-1
MAGED2	ENST00000375058.5	TSL:1	c.128C>T	p.Pro43Leu	missense	Exon 3 of 13	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

110746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000692

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000284

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000843

AC:

AN:

166019

AF XY:

0.0000561

show subpopulations

Gnomad AFR exome

AF:

0.000505

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000416

Gnomad OTH exome

AF:

0.000238

GnomAD4 exome

AF:

0.0000284

AC:

AN:

1090945

Hom.:

Cov.:

AF XY:

0.0000252

AC XY:

AN XY:

357341

show subpopulations

African (AFR)

AF:

0.000533

AC:

AN:

26280

American (AMR)

AF:

0.000204

AC:

AN:

34356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19245

East Asian (EAS)

AF:

0.00

AC:

AN:

29934

South Asian (SAS)

AF:

0.00

AC:

AN:

52897

European-Finnish (FIN)

AF:

0.0000249

AC:

AN:

40085

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.00000716

AC:

AN:

838167

Other (OTH)

AF:

0.0000654

AC:

AN:

45860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000244

AC:

AN:

110801

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

33041

show subpopulations

African (AFR)

AF:

0.000691

AC:

AN:

30399

American (AMR)

AF:

0.000286

AC:

AN:

10497

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.000285

AC:

AN:

3508

South Asian (SAS)

AF:

0.00

AC:

AN:

2539

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52861

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000108

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000908

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.9

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.19

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.61

M_CAP

Benign

0.0047

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.19

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.026

Sift

Benign

0.076

Sift4G

Uncertain

0.0070

Polyphen

0.036

Vest4

0.14

MVP

0.19

MPC

0.62

ClinPred

0.0089

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.073

gMVP

0.15

Mutation Taster

=100/0

polymorphism

(source)

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