rs61753982

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001110792.2(MECP2):c.414-17delT variant causes a intron change. The variant allele was found at a frequency of 0.00563 in 1,209,376 control chromosomes in the GnomAD database, including 19 homozygotes. There are 2,150 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., 145 hem., cov: 22)

Exomes 𝑓: 0.0058 ( 16 hom. 2005 hem. )

Consequence

MECP2
NM_001110792.2 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 4.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant X-154031466-GA-G is Benign according to our data. Variant chrX-154031466-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 156063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031466-GA-G is described in Lovd as [Likely_benign]. Variant chrX-154031466-GA-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00438 (492/112275) while in subpopulation NFE AF= 0.0066 (351/53189). AF 95% confidence interval is 0.00603. There are 3 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.414-17delT		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.378-17delT		intron_variant	Intron 3 of 3	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.414-17delT		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.378-17delT		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00438

AC:

492

AN:

112221

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

145

AN XY:

34377

show subpopulations

Gnomad AFR

AF:

0.000745

Gnomad AMI

AF:

0.00293

Gnomad AMR

AF:

0.00377

Gnomad ASJ

AF:

0.00679

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00767

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.00663

GnomAD3 exomes

AF:

0.00432

AC:

782

AN:

181154

Hom.:

AF XY:

0.00408

AC XY:

274

AN XY:

67132

show subpopulations

Gnomad AFR exome

AF:

0.000614

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00522

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00567

Gnomad OTH exome

AF:

0.00601

GnomAD4 exome

AF:

0.00576

AC:

6319

AN:

1097101

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

2005

AN XY:

362565

show subpopulations

Gnomad4 AFR exome

AF:

0.000417

Gnomad4 AMR exome

AF:

0.00287

Gnomad4 ASJ exome

AF:

0.00609

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.00647

Gnomad4 OTH exome

AF:

0.00415

GnomAD4 genome

AF:

0.00438

AC:

492

AN:

112275

Hom.:

Cov.:

AF XY:

0.00421

AC XY:

145

AN XY:

34441

show subpopulations

Gnomad4 AFR

AF:

0.000743

Gnomad4 AMR

AF:

0.00376

Gnomad4 ASJ

AF:

0.00679

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00767

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.00654

Alfa

AF:

0.00523

Hom.:

Bravo

AF:

0.00430

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Jun 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2013

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome

Benign:2

Aug 14, 2023

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 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). -

Jun 01, 2018

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 23, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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