rs878854407

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_177433.3(MAGED2):c.1336C>T(p.Arg446Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MAGED2
NM_177433.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.33

Variant links:

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 links:

SNORA11 (HGNC:32599): (small nucleolar RNA, H/ACA box 11) Small nucleolar RNAs (snoRNAs) are small noncoding RNAs involved in RNA processing. Box H/ACA snoRNAs, such as SNORA11, direct the conversion of uridine to pseudouridine at specific residues of ribosomal RNAs or small nuclear RNAs (snRNAs) (Gu et al., 2005).[supplied by OMIM, Mar 2008]

SNORA11 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant X-54814725-C-T is Pathogenic according to our data. Variant chrX-54814725-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226034.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-54814725-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGED2	NM_177433.3 link	c.1336C>T	p.Arg446Cys	missense_variant	Exon 11 of 13	ENST00000375068.6	NP_803182.1	Q9UNF1-1A0A024R9Y7
MAGED2	NM_014599.6 link	c.1336C>T	p.Arg446Cys	missense_variant	Exon 11 of 13		NP_055414.2	Q9UNF1-1A0A024R9Y7
MAGED2	NM_201222.3 link	c.1336C>T	p.Arg446Cys	missense_variant	Exon 11 of 13		NP_957516.1	Q9UNF1-1A0A024R9Y7
SNORA11	NR_002953.1 link	n.*225C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6 link	c.1336C>T	p.Arg446Cys	missense_variant	Exon 11 of 13	1	NM_177433.3	ENSP00000364209.1		Q9UNF1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1097405

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362771

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bartter disease type 5

Pathogenic:1

Sep 23, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Nov 09, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32529326, 27120771, 29146702, 28973533, 34926352) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;T;T;T;T;T;T

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.94

.;D;.;D;D;.;.;.

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Pathogenic

4.0

H;.;H;.;H;H;.;H

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.0

D;.;D;.;D;D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.015

D;.;D;.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;D;D;D;D

Vest4

0.90

MutPred

0.94

Loss of MoRF binding (P = 0.0088);.;Loss of MoRF binding (P = 0.0088);.;Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);.;Loss of MoRF binding (P = 0.0088);

MVP

0.78

MPC

1.7

ClinPred

1.0

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over