chrX-154030594-C-T

Position:

chrX-154030594-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000453960.7(MECP2):c.1270G>A(p.Val424Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,204,116 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V424A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.00021 ( 0 hom. 121 hem. )

Consequence

MECP2
ENST00000453960.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.363

Variant links:

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071368515).

BP6

Variant X-154030594-C-T is Benign according to our data. Variant chrX-154030594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 143446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030594-C-T is described in Lovd as [Likely_benign]. Variant chrX-154030594-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000147 (16/108707) while in subpopulation SAS AF= 0.00249 (6/2407). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1270G>A	p.Val424Ile	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.1234G>A	p.Val412Ile	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1270G>A	p.Val424Ile	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1234G>A	p.Val412Ile	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000628176.2 linkuse as main transcript	c.*606G>A		3_prime_UTR_variant	5/5	3		ENSP00000486978
MECP2	ENST00000407218.5 linkuse as main transcript			downstream_gene_variant		5		ENSP00000384865

Frequencies

GnomAD3 genomes

AF:

0.000147

AC:

AN:

108662

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

31064

show subpopulations

Gnomad AFR

AF:

0.0000671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000289

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000176

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000958

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000449

AC:

AN:

180258

Hom.:

AF XY:

0.000684

AC XY:

AN XY:

65744

show subpopulations

Gnomad AFR exome

AF:

0.0000767

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000214

AC:

234

AN:

1095409

Hom.:

Cov.:

AF XY:

0.000335

AC XY:

121

AN XY:

361687

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.000530

Gnomad4 SAS exome

AF:

0.00249

Gnomad4 FIN exome

AF:

0.000104

Gnomad4 NFE exome

AF:

0.0000760

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000147

AC:

AN:

108707

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

31119

show subpopulations

Gnomad4 AFR

AF:

0.0000670

Gnomad4 AMR

AF:

0.0000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000290

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.000176

Gnomad4 NFE

AF:

0.0000958

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000109

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2017	- -
Benign, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2016	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	This variant is associated with the following publications: (PMID: 12872250, 11055898, 24715477, 23810759) -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Rett syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Aug 14, 2023

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria.Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

3.3

DANN

Benign

0.93

DEOGEN2

Benign

0.30

T;.

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.20

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.10

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.59

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0

B;B

Vest4

0.020

MVP

0.92

ClinPred

0.011

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.11

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

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