rs760829080

Variant names:

• chrX-54809966-C-G
• rs760829080
• NM_177433.3:c.290C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_177433.3(MAGED2):​c.290C>G​(p.Ala97Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000824 in 1,092,147 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAGED2 NM_177433.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.98
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17905611).
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.290C>G	p.Ala97Gly	missense	Exon 3 of 13	NP_803182.1	Q9UNF1-1
	MAGED2	NM_014599.6		c.290C>G	p.Ala97Gly	missense	Exon 3 of 13	NP_055414.2
	MAGED2	NM_201222.3		c.290C>G	p.Ala97Gly	missense	Exon 3 of 13	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.290C>G	p.Ala97Gly	missense	Exon 3 of 13	ENSP00000364209.1	Q9UNF1-1
	MAGED2	ENST00000375053.6	TSL:1	c.290C>G	p.Ala97Gly	missense	Exon 3 of 12	ENSP00000364193.2	Q9UNF1-1
	MAGED2	ENST00000375058.5	TSL:1	c.290C>G	p.Ala97Gly	missense	Exon 3 of 13	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111204 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 9 AN: 1092147 Hom.: 0 Cov.: 34 AF XY: 0.0000112 AC XY: 4 AN XY: 358543

African (AFR) AF: 0.00 AC: 0 AN: 26354

American (AMR) AF: 0.00 AC: 0 AN: 34529

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19235

East Asian (EAS) AF: 0.00 AC: 0 AN: 30086

South Asian (SAS) AF: 0.00 AC: 0 AN: 53085

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000835 AC: 7 AN: 838729

Other (OTH) AF: 0.0000436 AC: 2 AN: 45910

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 111204 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33380

African (AFR) AF: 0.00 AC: 0 AN: 30488

American (AMR) AF: 0.00 AC: 0 AN: 10552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2559

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6017

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52979

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.020
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Polyphen		0.50	P
Vest4		0.13
MutPred		0.24		Loss of helix (P = 0.0068)
MVP		0.49
MPC		0.74
ClinPred		0.22	T
GERP RS		3.5
Varity_R		0.17
gMVP		0.048
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs760829080; hg19: chrX-54836399;