X-154097618-GCCT-GCCTCCT

Position:

chrX-154097618-GCCT-GCCTCCT

Variant summary

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

The NM_001110792.2(MECP2):c.45_47dupAGG(p.Gly16dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,028,331 control chromosomes in the GnomAD database, including 3 homozygotes. There are 420 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., 38 hem., cov: 20)

Exomes 𝑓: 0.0018 ( 3 hom. 382 hem. )

Consequence

MECP2
NM_001110792.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:9

Conservation

PhyloP100: 1.66

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:

MECP2 (HGNC:):

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-154097618-G-GCCT is Benign according to our data. Variant chrX-154097618-G-GCCT is described in ClinVar as [Benign]. Clinvar id is 158882.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00181 (189/104220) while in subpopulation AFR AF= 0.00331 (96/29030). AF 95% confidence interval is 0.00277. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.45_47dupAGG	p.Gly16dup	disruptive_inframe_insertion	1/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.-116_-114dupAGG		5_prime_UTR_variant	1/4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.45_47dupAGG	p.Gly16dup	disruptive_inframe_insertion	1/3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.-116_-114dupAGG		5_prime_UTR_variant	1/4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

189

AN:

104180

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

28794

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000593

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000320

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.00141

GnomAD3 exomes

AF:

0.000863

AC:

AN:

71845

Hom.:

AF XY:

0.000640

AC XY:

AN XY:

18751

show subpopulations

Gnomad AFR exome

AF:

0.00297

Gnomad AMR exome

AF:

0.000343

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000212

Gnomad SAS exome

AF:

0.000695

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.000617

GnomAD4 exome

AF:

0.00182

AC:

1683

AN:

924111

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

382

AN XY:

284099

show subpopulations

Gnomad4 AFR exome

AF:

0.00219

Gnomad4 AMR exome

AF:

0.000445

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000924

Gnomad4 SAS exome

AF:

0.00120

Gnomad4 FIN exome

AF:

0.000186

Gnomad4 NFE exome

AF:

0.00202

Gnomad4 OTH exome

AF:

0.00176

GnomAD4 genome

AF:

0.00181

AC:

189

AN:

104220

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

28838

show subpopulations

Gnomad4 AFR

AF:

0.00331

Gnomad4 AMR

AF:

0.000592

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000321

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00168

Gnomad4 OTH

AF:

0.00139

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	curation	RettBASE	May 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Sep 24, 2020	- -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Rett syndrome

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 08, 2022	The allele frequency of the c.-116_-114dup variant in MECP2 (NM_004992.3) is 0.28% in African/African American sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The c.-116_-114dup variant is observed in at least 2 unaffected individuals (RettBASE) (BS2). In summary, the c.-116_-114dup variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). -
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 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

May 31, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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