chrX-30218623-C-T

Variant names:

• chrX-30218623-C-T
• rs747224013
• NM_002364.5:c.43C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_002364.5(MAGEB2):​c.43C>T​(p.Arg15Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000563 in 1,208,787 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000057 (0 hom. 25 hem.)
• Consequence: MAGEB2 NM_002364.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0480
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14228201).
• BP6: Variant X-30218623-C-T is Benign according to our data. Variant chrX-30218623-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2375978.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEB2	NM_002364.5	MANE Select	c.43C>T	p.Arg15Cys	missense	Exon 2 of 2	NP_002355.2	O15479

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEB2	ENST00000378988.5	TSL:1 MANE Select	c.43C>T	p.Arg15Cys	missense	Exon 2 of 2	ENSP00000368273.4	O15479

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112198 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000444 AC: 8 AN: 180076 AF XY: 0.0000309

Gnomad AFR exome AF: 0.0000768

Gnomad AMR exome AF: 0.0000372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000575 AC: 63 AN: 1096589 Hom.: 0 Cov.: 32 AF XY: 0.0000690 AC XY: 25 AN XY: 362057

African (AFR) AF: 0.00 AC: 0 AN: 26345

American (AMR) AF: 0.0000572 AC: 2 AN: 34993

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19288

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30188

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.0000689 AC: 58 AN: 841372

Other (OTH) AF: 0.0000217 AC: 1 AN: 46000

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112198 Hom.: 0 Cov.: 23 AF XY: 0.0000582 AC XY: 2 AN XY: 34368

African (AFR) AF: 0.0000973 AC: 3 AN: 30848

American (AMR) AF: 0.00 AC: 0 AN: 10650

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53219

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.072	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.048
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Benign	0.053
Sift	Benign	0.10	T
Sift4G	Uncertain	0.045	D
Polyphen		0.98	D
Vest4		0.18
MVP		0.25
MPC		0.0071
ClinPred		0.32	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.34
gMVP		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747224013; hg19: chrX-30236740;