X-54810072-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.396A>G(p.Thr132=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,203,510 control chromosomes in the GnomAD database, including 60,298 homozygotes. There are 145,279 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (8802 hom., 13642 hem., cov: 21)
  • Exomes 𝑓: 0.37 (51496 hom. 131637 hem.)
• Consequence: MAGED2 NM_177433.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.75

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=-1.01).
• BP6: Variant X-54810072-A-G is Benign according to our data. Variant chrX-54810072-A-G is described in ClinVar as [Benign]. Clinvar id is 1258035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54810072-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED2	NM_177433.3	c.396A>G	p.Thr132=	synonymous_variant	3/13	ENST00000375068.6
MAGED2	NM_014599.6	c.396A>G	p.Thr132=	synonymous_variant	3/13
MAGED2	NM_201222.3	c.396A>G	p.Thr132=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED2	ENST00000375068.6	c.396A>G	p.Thr132=	synonymous_variant	3/13	1	NM_177433.3	P1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 48518 AN: 108902 Hom.: 8808 Cov.: 21 AF XY: 0.435 AC XY: 13592 AN XY: 31246

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.618

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.270

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.411

GnomAD3 exomes AF: 0.400 AC: 69792 AN: 174666 Hom.: 10295 AF XY: 0.383 AC XY: 23198 AN XY: 60506

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.629

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.366 AC: 400152 AN: 1094553 Hom.: 51496 Cov.: 33 AF XY: 0.365 AC XY: 131637 AN XY: 360431

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.377

GnomAD4 genome AF: 0.446 AC: 48552 AN: 108957 Hom.: 8802 Cov.: 21 AF XY: 0.436 AC XY: 13642 AN XY: 31311

Gnomad4 AFR AF: 0.669

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.406

Alfa AF: 0.362 Hom.: 16996

Bravo AF: 0.461

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

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	-1.0
Cadd	Benign	2.5
Dann	Benign	0.67

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: rs1043034; hg19: chrX-54836505; COSMIC: COSV54497791; COSMIC: COSV54497791;