X-30219073-G-T

Variant names:

• chrX-30219073-G-T
• rs1924487974
• NM_002364.5:c.493G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_002364.5(MAGEB2):​c.493G>T​(p.Gly165Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,096,944 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: MAGEB2 NM_002364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

Genes affected

MAGEB2 (HGNC:6809): (MAGE family member B2) This gene is a member of the MAGEB gene family. The members of this family have their entire coding sequences located in the last exon, and the encoded proteins show 50 to 68% sequence identity to each other. The promoters and first exons of the MAGEB genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. This gene is localized in the DSS (dosage-sensitive sex reversal) critical region. It is expressed in testis and placenta, and in a significant fraction of tumors of various histological types. The MAGEB genes are clustered on chromosome Xp22-p21. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB2	NM_002364.5	c.493G>T	p.Gly165Cys	missense_variant	Exon 2 of 2	ENST00000378988.5	NP_002355.2
MAGEB2	XM_011545512.2	c.493G>T	p.Gly165Cys	missense_variant	Exon 2 of 2		XP_011543814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEB2	ENST00000378988.5	c.493G>T	p.Gly165Cys	missense_variant	Exon 2 of 2	1	NM_002364.5	ENSP00000368273.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1096944 Hom.: 0 Cov.: 33 AF XY: 0.00000552 AC XY: 2 AN XY: 362336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493G>T (p.G165C) alteration is located in exon 2 (coding exon 1) of the MAGEB2 gene. This alteration results from a G to T substitution at nucleotide position 493, causing the glycine (G) at amino acid position 165 to be replaced by a cysteine (C). 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.95		Loss of ubiquitination at K170 (P = 0.0777);
MVP		0.38
MPC		0.0083
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.87
gMVP		0.81

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: rs1924487974; hg19: chrX-30237190;