Variant X-154097642-CGCGGCGGCG-CGCG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_StrongBS2

The NM_001110792.2(MECP2):c.18_23del(p.Ala7_Ala8del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000381 in 1,024,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000036 ( 0 hom. 4 hem. )

Consequence

MECP2
NM_001110792.2 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:3

Conservation

PhyloP100: 4.00

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 -8 ACMG points.

BP6

Variant X-154097642-CGCGGCG-C is Benign according to our data. Variant chrX-154097642-CGCGGCG-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 156657.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chrX-154097642-CGCGGCG-C is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.18_23del	p.Ala7_Ala8del	inframe_deletion	1/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.-143_-138del		5_prime_UTR_variant	1/4	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.18_23del	p.Ala7_Ala8del	inframe_deletion	1/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.-143_-138del		5_prime_UTR_variant	1/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000563

AC:

AN:

106552

Hom.:

Cov.:

AF XY:

0.0000994

AC XY:

AN XY:

30188

show subpopulations

Gnomad AFR

AF:

0.000101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000307

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000197

Gnomad OTH

AF:

0.000695

GnomAD4 exome

AF:

0.0000360

AC:

AN:

917924

Hom.:

AF XY:

0.0000140

AC XY:

AN XY:

284702

show subpopulations

Gnomad4 AFR exome

AF:

0.000202

Gnomad4 AMR exome

AF:

0.0000585

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000315

Gnomad4 FIN exome

AF:

0.0000463

Gnomad4 NFE exome

AF:

0.0000332

Gnomad4 OTH exome

AF:

0.0000271

GnomAD4 genome

AF:

0.0000563

AC:

AN:

106585

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

30233

show subpopulations

Gnomad4 AFR

AF:

0.000101

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000308

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000197

Gnomad4 OTH

AF:

0.000686

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Uncertain:1Benign:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Apr 28, 2022	The p.Ala7_Ala8del variant in MECP2 (NM_001110792.2) is present in 1 male individual in gnomAD (0.006%) (not sufficient to meet BS1 criteria). Larger deletions encompassing this region (p.Ala6_Ala8del) have been observed in an unaffected mother and father (Invitae internal database) (BP3). This variant has been observed in an individual with neurodevelopment disorder (PMID 1717659) (not sufficient for PS4_supporting). The p.Ala7_Ala8del variant is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. In summary, the p.Ala7_Ala8del variant in MECP2 is classified as a variant of unknown significance based on the ACMG/AMP criteria (BP3). -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 16, 2024	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 3.0, 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 between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Nov 01, 2007

- -

MECP2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2024

The MECP2 c.18_23del6 variant is predicted to result in an in-frame deletion (p.Ala7_Ala8del). This variant has been reported in an individual with intellectual disability (Harvey et al. 2007. PubMed ID: 17171659). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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