X-54810017-A-T

Variant names:

• chrX-54810017-A-T
• rs185932631
• NM_177433.3:c.341A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_177433.3(MAGED2):​c.341A>T​(p.Gln114Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,205,060 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q114R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: MAGED2 NM_177433.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 1 publications found

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]

MAGED2 Gene-Disease associations (from GenCC):

• Bartter disease type 5

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• antenatal Bartter syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.112247795).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177433.3. 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
	MAGED2	NM_177433.3	MANE Select	c.341A>T	p.Gln114Leu	missense	Exon 3 of 13	NP_803182.1	Q9UNF1-1
	MAGED2	NM_014599.6		c.341A>T	p.Gln114Leu	missense	Exon 3 of 13	NP_055414.2
	MAGED2	NM_201222.3		c.341A>T	p.Gln114Leu	missense	Exon 3 of 13	NP_957516.1	Q9UNF1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGED2	ENST00000375068.6	TSL:1 MANE Select	c.341A>T	p.Gln114Leu	missense	Exon 3 of 13	ENSP00000364209.1	Q9UNF1-1
	MAGED2	ENST00000375053.6	TSL:1	c.341A>T	p.Gln114Leu	missense	Exon 3 of 12	ENSP00000364193.2	Q9UNF1-1
	MAGED2	ENST00000375058.5	TSL:1	c.341A>T	p.Gln114Leu	missense	Exon 3 of 13	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110753 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000580 AC: 1 AN: 172511 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000731 AC: 8 AN: 1094307 Hom.: 0 Cov.: 34 AF XY: 0.00000555 AC XY: 2 AN XY: 360241

African (AFR) AF: 0.00 AC: 0 AN: 26364

American (AMR) AF: 0.00 AC: 0 AN: 34828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19270

East Asian (EAS) AF: 0.00 AC: 0 AN: 30161

South Asian (SAS) AF: 0.00 AC: 0 AN: 53431

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000952 AC: 8 AN: 839998

Other (OTH) AF: 0.00 AC: 0 AN: 45977

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110753 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32931

African (AFR) AF: 0.00 AC: 0 AN: 30378

American (AMR) AF: 0.00 AC: 0 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6017

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52790

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.0000261 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.013
Sift	Benign	0.31	T
Sift4G	Benign	0.28	T
Polyphen		0.50	P
Vest4		0.24
MutPred		0.23		Loss of solvent accessibility (P = 0.0635)
MVP		0.32
MPC		0.68
ClinPred		0.16	T
GERP RS		3.2
Varity_R		0.12
gMVP		0.24
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs185932631; hg19: chrX-54836450;