X-54809804-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_177433.3(MAGED2):c.128C>T(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,201,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000028 (0 hom. 9 hem.)
• Consequence: MAGED2 NM_177433.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.186

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028511912).
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED2	NM_177433.3	c.128C>T	p.Pro43Leu	missense_variant	3/13	ENST00000375068.6
MAGED2	NM_014599.6	c.128C>T	p.Pro43Leu	missense_variant	3/13
MAGED2	NM_201222.3	c.128C>T	p.Pro43Leu	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED2	ENST00000375068.6	c.128C>T	p.Pro43Leu	missense_variant	3/13	1	NM_177433.3	P1

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 27 AN: 110746 Hom.: 0 Cov.: 22 AF XY: 0.000152 AC XY: 5 AN XY: 32976

Gnomad AFR AF: 0.000692

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000843 AC: 14 AN: 166019 Hom.: 0 AF XY: 0.0000561 AC XY: 3 AN XY: 53499

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000416

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.0000284 AC: 31 AN: 1090945 Hom.: 0 Cov.: 31 AF XY: 0.0000252 AC XY: 9 AN XY: 357341

Gnomad4 AFR exome AF: 0.000533

Gnomad4 AMR exome AF: 0.000204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000249

Gnomad4 NFE exome AF: 0.00000716

Gnomad4 OTH exome AF: 0.0000654

GnomAD4 genome AF: 0.000244 AC: 27 AN: 110801 Hom.: 0 Cov.: 22 AF XY: 0.000151 AC XY: 5 AN XY: 33041

Gnomad4 AFR AF: 0.000691

Gnomad4 AMR AF: 0.000286

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000285

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000585 Hom.: 4

Bravo AF: 0.000351

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000908 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.128C>T (p.P43L) alteration is located in exon 3 (coding exon 2) of the MAGED2 gene. This alteration results from a C to T substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.9
Dann	Benign	0.97
DEOGEN2	Benign	0.19	T;T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.049	N
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.029	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;N;.;N;N;.;N
MutationTaster	Benign	1.0	A;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.2	D;.;D;.;D;D;N;D
REVEL	Benign	0.026
Sift	Benign	0.076	T;.;T;.;T;T;T;T
Sift4G	Uncertain	0.0070	D;D;D;T;D;D;D;D
Polyphen		0.036	B;B;B;.;B;B;B;B
Vest4		0.14
MVP		0.19
MPC		0.62
ClinPred		0.0089	T
GERP RS		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.15

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: rs201160051; hg19: chrX-54836237; COSMIC: COSV99514592; COSMIC: COSV99514592;