Genetic Variant NM_177433.3:c.397A>G (chrX-54810073-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_177433.3(MAGED2):c.397A>G(p.Lys133Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

MAGED2
NM_177433.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.25

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14678416).

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.397A>G	p.Lys133Glu	missense	Exon 3 of 13	NP_803182.1	Q9UNF1-1
MAGED2	NM_014599.6		c.397A>G	p.Lys133Glu	missense	Exon 3 of 13	NP_055414.2
MAGED2	NM_201222.3		c.397A>G	p.Lys133Glu	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.397A>G	p.Lys133Glu	missense	Exon 3 of 13	ENSP00000364209.1	Q9UNF1-1
MAGED2	ENST00000375053.6	TSL:1	c.397A>G	p.Lys133Glu	missense	Exon 3 of 12	ENSP00000364193.2	Q9UNF1-1
MAGED2	ENST00000375058.5	TSL:1	c.397A>G	p.Lys133Glu	missense	Exon 3 of 13	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000566

AC:

AN:

176716

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000183

AC:

AN:

1095857

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361409

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26370

American (AMR)

AF:

0.0000285

AC:

AN:

35056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19316

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30190

South Asian (SAS)

AF:

0.00

AC:

AN:

53712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840765

Other (OTH)

AF:

0.00

AC:

AN:

46023

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.82

M_CAP

Benign

0.0098

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

PhyloP100

2.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.15

REVEL

Benign

0.0090

Sift

Uncertain

0.0020

Sift4G

Benign

0.75

Polyphen

0.28

Vest4

0.19

MutPred

0.28

Loss of ubiquitination at K133 (P = 0.0027)

MVP

0.42

MPC

0.99

ClinPred

0.17

GERP RS

3.1

Varity_R

0.16

gMVP

0.30

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over