chrX-30218657-A-G

Variant names:

• chrX-30218657-A-G
• rs139121250
• NM_002364.5:c.77A>G

Variant summary

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

The NM_002364.5(MAGEB2):​c.77A>G​(p.Asn26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,208,927 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., 20 hem., cov: 23)
  • Exomes 𝑓: 0.00045 (0 hom. 161 hem.)
• Consequence: MAGEB2 NM_002364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.36

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004267305).
• BS2: High Hemizygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB2	NM_002364.5	c.77A>G	p.Asn26Ser	missense_variant	Exon 2 of 2	ENST00000378988.5	NP_002355.2
MAGEB2	XM_011545512.2	c.77A>G	p.Asn26Ser	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.77A>G	p.Asn26Ser	missense_variant	Exon 2 of 2	1	NM_002364.5	ENSP00000368273.4

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 93 AN: 112296 Hom.: 0 Cov.: 23 AF XY: 0.000580 AC XY: 20 AN XY: 34478

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000468

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000564

Gnomad OTH AF: 0.000660

GnomAD3 exomes AF: 0.000549 AC: 98 AN: 178473 Hom.: 0 AF XY: 0.000475 AC XY: 30 AN XY: 63149

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000220

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000382

Gnomad NFE exome AF: 0.000645

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000449 AC: 492 AN: 1096572 Hom.: 0 Cov.: 32 AF XY: 0.000445 AC XY: 161 AN XY: 361974

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000994

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.000396

Gnomad4 NFE exome AF: 0.000478

Gnomad4 OTH exome AF: 0.000369

GnomAD4 genome AF: 0.000828 AC: 93 AN: 112355 Hom.: 0 Cov.: 23 AF XY: 0.000579 AC XY: 20 AN XY: 34547

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.000468

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.000375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000564

Gnomad4 OTH AF: 0.000652

Alfa AF: 0.000614 Hom.: 29

Bravo AF: 0.000880

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000618 AC: 75

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77A>G (p.N26S) alteration is located in exon 2 (coding exon 1) of the MAGEB2 gene. This alteration results from a A to G substitution at nucleotide position 77, causing the asparagine (N) at amino acid position 26 to be replaced by a serine (S). 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	0.071
BayesDel_addAF	Benign	-0.98	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.0010
DANN	Benign	0.25
DEOGEN2	Benign	0.0045	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.021
Sift	Benign	0.50	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.045
MVP		0.17
MPC		0.0030
ClinPred		0.0065	T
GERP RS		-3.5
Varity_R		0.031
gMVP		0.053

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: rs139121250; hg19: chrX-30236774;