X-54809928-A-G

Variant names:

• chrX-54809928-A-G
• rs1043031
• NM_177433.3:c.252A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_177433.3(MAGED2):​c.252A>G​(p.Ser84Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,196,048 control chromosomes in the GnomAD database, including 51,377 homozygotes. There are 137,072 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S84S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (4686 hom., 10959 hem., cov: 21)
  • Exomes 𝑓: 0.35 (46691 hom. 126113 hem.)
• Consequence: MAGED2 NM_177433.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.10
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-54809928-A-G is Benign according to our data. Variant chrX-54809928-A-G is described in ClinVar as Benign. ClinVar VariationId is 1244776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

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.252A>G	p.Ser84Ser	synonymous	Exon 3 of 13	NP_803182.1	Q9UNF1-1
	MAGED2	NM_014599.6		c.252A>G	p.Ser84Ser	synonymous	Exon 3 of 13	NP_055414.2
	MAGED2	NM_201222.3		c.252A>G	p.Ser84Ser	synonymous	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.252A>G	p.Ser84Ser	synonymous	Exon 3 of 13	ENSP00000364209.1	Q9UNF1-1
	MAGED2	ENST00000375053.6	TSL:1	c.252A>G	p.Ser84Ser	synonymous	Exon 3 of 12	ENSP00000364193.2	Q9UNF1-1
	MAGED2	ENST00000375058.5	TSL:1	c.252A>G	p.Ser84Ser	synonymous	Exon 3 of 13	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 37391 AN: 109663 Hom.: 4698 Cov.: 21

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.367 AC: 57632 AN: 157094 AF XY: 0.361

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.398

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.353 AC: 383735 AN: 1086329 Hom.: 46691 Cov.: 34 AF XY: 0.355 AC XY: 126113 AN XY: 355205

African (AFR) AF: 0.303 AC: 7944 AN: 26257

American (AMR) AF: 0.336 AC: 11180 AN: 33299

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 7238 AN: 19136

East Asian (EAS) AF: 0.636 AC: 18975 AN: 29853

South Asian (SAS) AF: 0.388 AC: 20449 AN: 52640

European-Finnish (FIN) AF: 0.403 AC: 15985 AN: 39680

Middle Eastern (MID) AF: 0.301 AC: 1236 AN: 4113

European-Non Finnish (NFE) AF: 0.341 AC: 284797 AN: 835698

Other (OTH) AF: 0.349 AC: 15931 AN: 45653

GnomAD4 genome AF: 0.341 AC: 37388 AN: 109719 Hom.: 4686 Cov.: 21 AF XY: 0.342 AC XY: 10959 AN XY: 32023

African (AFR) AF: 0.303 AC: 9154 AN: 30170

American (AMR) AF: 0.364 AC: 3791 AN: 10415

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 970 AN: 2607

East Asian (EAS) AF: 0.617 AC: 2114 AN: 3426

South Asian (SAS) AF: 0.367 AC: 905 AN: 2467

European-Finnish (FIN) AF: 0.397 AC: 2279 AN: 5738

Middle Eastern (MID) AF: 0.234 AC: 50 AN: 214

European-Non Finnish (NFE) AF: 0.334 AC: 17560 AN: 52507

Other (OTH) AF: 0.328 AC: 492 AN: 1500

Alfa AF: 0.337 Hom.: 19687

Bravo AF: 0.341

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Bartter disease type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.9
DANN	Benign	0.80
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1043031; hg19: chrX-54836361; COSMIC: COSV99514398; COSMIC: COSV99514398;