rs878854405

Variant names:

• chrX-54812155-A-G
• rs878854405
• NM_177433.3:c.991-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

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

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

ACMG classification

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 VariationId is 226032.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGED2	NM_177433.3	MANE Select	c.991-2A>G		splice_acceptor intron	N/A	NP_803182.1	Q9UNF1-1
	MAGED2	NM_014599.6		c.991-2A>G		splice_acceptor intron	N/A	NP_055414.2
	MAGED2	NM_201222.3		c.991-2A>G		splice_acceptor intron	N/A	NP_957516.1	Q9UNF1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGED2	ENST00000375068.6	TSL:1 MANE Select	c.991-2A>G		splice_acceptor intron	N/A	ENSP00000364209.1	Q9UNF1-1
	MAGED2	ENST00000375053.6	TSL:1	c.991-2A>G		splice_acceptor intron	N/A	ENSP00000364193.2	Q9UNF1-1
	MAGED2	ENST00000375058.5	TSL:1	c.991-2A>G		splice_acceptor intron	N/A	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.73e-7 AC: 1 AN: 1027391 Hom.: 0 Cov.: 19 AF XY: 0.00000319 AC XY: 1 AN XY: 313681

African (AFR) AF: 0.00 AC: 0 AN: 24983

American (AMR) AF: 0.00 AC: 0 AN: 34873

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18827

East Asian (EAS) AF: 0.00 AC: 0 AN: 29683

South Asian (SAS) AF: 0.00 AC: 0 AN: 52228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40221

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3962

European-Non Finnish (NFE) AF: 0.00000128 AC: 1 AN: 778924

Other (OTH) AF: 0.00 AC: 0 AN: 43690

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Bartter disease type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Benign	0.94
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.4
GERP RS		3.7
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878854405; hg19: chrX-54838588;