chrX-54809253-G-T

Variant names:

• chrX-54809253-G-T
• rs41309825
• NM_177433.3:c.-29-50G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_177433.3(MAGED2):​c.-29-50G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,021,108 control chromosomes in the GnomAD database, including 155 homozygotes. There are 5,141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (6 hom., 391 hem., cov: 23)
  • Exomes 𝑓: 0.019 (149 hom. 4750 hem.)
• Consequence: MAGED2 NM_177433.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.150
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-54809253-G-T is Benign according to our data. Variant chrX-54809253-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1213451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1349/111748) while in subpopulation NFE AF = 0.0198 (1051/53044). AF 95% confidence interval is 0.0188. There are 6 homozygotes in GnomAd4. There are 391 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGED2	NM_177433.3	MANE Select	c.-29-50G>T		intron	N/A	NP_803182.1	Q9UNF1-1
	MAGED2	NM_014599.6		c.-29-50G>T		intron	N/A	NP_055414.2
	MAGED2	NM_201222.3		c.-30+30G>T		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.-29-50G>T		intron	N/A	ENSP00000364209.1	Q9UNF1-1
	MAGED2	ENST00000375053.6	TSL:1	c.-29-50G>T		intron	N/A	ENSP00000364193.2	Q9UNF1-1
	MAGED2	ENST00000375058.5	TSL:1	c.-29-50G>T		intron	N/A	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1350 AN: 111691 Hom.: 6 Cov.: 23

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00604

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00262

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.00802

GnomAD4 exome AF: 0.0193 AC: 17515 AN: 909360 Hom.: 149 Cov.: 15 AF XY: 0.0184 AC XY: 4750 AN XY: 258300

African (AFR) AF: 0.00184 AC: 42 AN: 22866

American (AMR) AF: 0.00250 AC: 86 AN: 34443

Ashkenazi Jewish (ASJ) AF: 0.00713 AC: 129 AN: 18100

East Asian (EAS) AF: 0.00 AC: 0 AN: 29288

South Asian (SAS) AF: 0.00181 AC: 89 AN: 49090

European-Finnish (FIN) AF: 0.0248 AC: 991 AN: 39945

Middle Eastern (MID) AF: 0.00133 AC: 5 AN: 3755

European-Non Finnish (NFE) AF: 0.0232 AC: 15598 AN: 671971

Other (OTH) AF: 0.0144 AC: 575 AN: 39902

GnomAD4 genome AF: 0.0121 AC: 1349 AN: 111748 Hom.: 6 Cov.: 23 AF XY: 0.0115 AC XY: 391 AN XY: 33936

African (AFR) AF: 0.00276 AC: 85 AN: 30757

American (AMR) AF: 0.00348 AC: 37 AN: 10635

Ashkenazi Jewish (ASJ) AF: 0.00604 AC: 16 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00225 AC: 6 AN: 2662

European-Finnish (FIN) AF: 0.0235 AC: 142 AN: 6043

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0198 AC: 1051 AN: 53044

Other (OTH) AF: 0.00791 AC: 12 AN: 1517

Alfa AF: 0.0176 Hom.: 101

Bravo AF: 0.0103

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.7
DANN	Benign	0.68
PhyloP100		0.15
PromoterAI		-0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41309825; hg19: chrX-54835686;