Genetic Variant NM_177433.3:c.991-2A>G (chrX-54812155-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_177433.3(MAGED2):c.991-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.7e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

MAGED2
NM_177433.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.44

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: STRONG Submitted by: 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: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.052169137 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 21, new splice context is: tatttgggattcaattgaAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-54812155-A-G is Pathogenic according to our data. Variant chrX-54812155-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 226032.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MAGED2	NM_177433.3 link	c.991-2A>G	splice_acceptor_variant, intron_variant	Intron 6 of 12	ENST00000375068.6	NP_803182.1	Q9UNF1-1A0A024R9Y7
MAGED2	NM_014599.6 link	c.991-2A>G	splice_acceptor_variant, intron_variant	Intron 6 of 12		NP_055414.2	Q9UNF1-1A0A024R9Y7
MAGED2	NM_201222.3 link	c.991-2A>G	splice_acceptor_variant, intron_variant	Intron 6 of 12		NP_957516.1	Q9UNF1-1A0A024R9Y7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6 link	c.991-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 12	1	NM_177433.3	ENSP00000364209.1		Q9UNF1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.73e-7

AC:

AN:

1027391

Hom.:

Cov.:

AF XY:

0.00000319

AC XY:

AN XY:

313681

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24983

American (AMR)

AF:

0.00

AC:

AN:

34873

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18827

East Asian (EAS)

AF:

0.00

AC:

AN:

29683

South Asian (SAS)

AF:

0.00

AC:

AN:

52228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40221

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.00000128

AC:

AN:

778924

Other (OTH)

AF:

0.00

AC:

AN:

43690

Age Distribution

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Bartter disease type 5

Pathogenic:1

Sep 23, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Benign

0.94

FATHMM_MKL

Uncertain

0.96

PhyloP100

6.4

GERP RS

3.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.98

Position offset: 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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over