X-54809928-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_177433.3(MAGED2):c.252A>G(p.Ser84=) 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 (★★).

• 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:3
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1244776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54809928-A-G is described in Lovd as [Likely_benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED2	NM_177433.3	c.252A>G	p.Ser84=	synonymous_variant	3/13	ENST00000375068.6
MAGED2	NM_014599.6	c.252A>G	p.Ser84=	synonymous_variant	3/13
MAGED2	NM_201222.3	c.252A>G	p.Ser84=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED2	ENST00000375068.6	c.252A>G	p.Ser84=	synonymous_variant	3/13	1	NM_177433.3	P1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 37391 AN: 109663 Hom.: 4698 Cov.: 21 AF XY: 0.342 AC XY: 10935 AN XY: 31957

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

GnomAD3 exomes AF: 0.367 AC: 57632 AN: 157094 Hom.: 7775 AF XY: 0.361 AC XY: 17544 AN XY: 48626

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 SAS exome AF: 0.386

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

Gnomad4 AFR exome AF: 0.303

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.378

Gnomad4 EAS exome AF: 0.636

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.341

Gnomad4 OTH exome AF: 0.349

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

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.328

Alfa AF: 0.338 Hom.: 15443

Bravo AF: 0.341

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Bartter disease type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	9.9
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

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