chrX-54809901-T-C

Variant names:

• chrX-54809901-T-C
• rs144346983
• NM_177433.3:c.225T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_177433.3(MAGED2):​c.225T>C​(p.Ala75Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,191,064 control chromosomes in the GnomAD database, including 5 homozygotes. There are 239 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., 115 hem., cov: 22)
  • Exomes 𝑓: 0.00042 (1 hom. 124 hem.)
• Consequence: MAGED2 NM_177433.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.189
• Publications: 0 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-54809901-T-C is Benign according to our data. Variant chrX-54809901-T-C is described in ClinVar as Benign. ClinVar VariationId is 721675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.189 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 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.225T>C	p.Ala75Ala	synonymous	Exon 3 of 13	NP_803182.1	Q9UNF1-1
	MAGED2	NM_014599.6		c.225T>C	p.Ala75Ala	synonymous	Exon 3 of 13	NP_055414.2
	MAGED2	NM_201222.3		c.225T>C	p.Ala75Ala	synonymous	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.225T>C	p.Ala75Ala	synonymous	Exon 3 of 13	ENSP00000364209.1	Q9UNF1-1
	MAGED2	ENST00000375053.6	TSL:1	c.225T>C	p.Ala75Ala	synonymous	Exon 3 of 12	ENSP00000364193.2	Q9UNF1-1
	MAGED2	ENST00000375058.5	TSL:1	c.225T>C	p.Ala75Ala	synonymous	Exon 3 of 13	ENSP00000364198.1	Q9UNF1-1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 453 AN: 110165 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000402

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00741

GnomAD2 exomes AF: 0.00116 AC: 172 AN: 148526 AF XY: 0.000799

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000930

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000639

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000416 AC: 450 AN: 1080847 Hom.: 1 Cov.: 31 AF XY: 0.000353 AC XY: 124 AN XY: 351453

African (AFR) AF: 0.0129 AC: 337 AN: 26079

American (AMR) AF: 0.000865 AC: 28 AN: 32383

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18998

East Asian (EAS) AF: 0.00 AC: 0 AN: 29543

South Asian (SAS) AF: 0.0000384 AC: 2 AN: 52066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39262

Middle Eastern (MID) AF: 0.000740 AC: 3 AN: 4053

European-Non Finnish (NFE) AF: 0.0000372 AC: 31 AN: 833027

Other (OTH) AF: 0.00108 AC: 49 AN: 45436

GnomAD4 genome AF: 0.00415 AC: 457 AN: 110217 Hom.: 4 Cov.: 22 AF XY: 0.00354 AC XY: 115 AN XY: 32511

African (AFR) AF: 0.0138 AC: 416 AN: 30240

American (AMR) AF: 0.00210 AC: 22 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3478

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5841

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000152 AC: 8 AN: 52675

Other (OTH) AF: 0.00732 AC: 11 AN: 1503

Alfa AF: 0.00208 Hom.: 9

Bravo AF: 0.00435

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs144346983; hg19: chrX-54836334;