X-54809806-A-G

Position:

• chrX-54809806-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_177433.3(MAGED2):​c.130A>G​(p.Lys44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,200,730 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,745 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., 74 hem., cov: 22)
  • Exomes 𝑓: 0.0047 (10 hom. 1671 hem.)
• Consequence: MAGED2 NM_177433.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.21

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052116513).
• BP6: Variant X-54809806-A-G is Benign according to our data. Variant chrX-54809806-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54809806-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 74 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGED2	NM_177433.3	c.130A>G	p.Lys44Glu	missense_variant	3/13	ENST00000375068.6	NP_803182.1
MAGED2	NM_014599.6	c.130A>G	p.Lys44Glu	missense_variant	3/13		NP_055414.2
MAGED2	NM_201222.3	c.130A>G	p.Lys44Glu	missense_variant	3/13		NP_957516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6	c.130A>G	p.Lys44Glu	missense_variant	3/13	1	NM_177433.3	ENSP00000364209	P1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 301 AN: 110849 Hom.: 1 Cov.: 22 AF XY: 0.00224 AC XY: 74 AN XY: 33061

Gnomad AFR AF: 0.000791

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000857

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000787

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00200

GnomAD3 exomes AF: 0.00317 AC: 520 AN: 163982 Hom.: 1 AF XY: 0.00340 AC XY: 177 AN XY: 52068

Gnomad AFR exome AF: 0.000682

Gnomad AMR exome AF: 0.000777

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.000820

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00474 AC: 5166 AN: 1089826 Hom.: 10 Cov.: 31 AF XY: 0.00469 AC XY: 1671 AN XY: 356358

Gnomad4 AFR exome AF: 0.000647

Gnomad4 AMR exome AF: 0.000731

Gnomad4 ASJ exome AF: 0.00208

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00571

Gnomad4 OTH exome AF: 0.00352

GnomAD4 genome AF: 0.00271 AC: 301 AN: 110904 Hom.: 1 Cov.: 22 AF XY: 0.00223 AC XY: 74 AN XY: 33126

Gnomad4 AFR AF: 0.000789

Gnomad4 AMR AF: 0.000856

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000788

Gnomad4 FIN AF: 0.00101

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00434 Hom.: 183

Bravo AF: 0.00263

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00554 AC: 16

ESP6500AA AF: 0.00156 AC: 6

ESP6500EA AF: 0.00505 AC: 34

ExAC AF: 0.00306 AC: 370

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 16, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.70	.;T;.;T;T;.;.;.
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0052	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;.;L;.;L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.43	N;.;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;.;D;D;D;D;T;D
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.98	D;P;D;.;D;D;P;D
Vest4		0.068
MVP		0.66
MPC		0.88
ClinPred		0.027	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.44

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: rs11555928; hg19: chrX-54836239;