X-154097608-TCTCCTCCTCGC-T

Variant names:

• chrX-154097608-TCTCCTCCTCGC-T
• rs786205042
• NM_001110792.2:c.47_57delGCGAGGAGGAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.47_57delGCGAGGAGGAG​(p.Gly16GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 402 pathogenic variants in the truncated region.
• PP5: Variant X-154097608-TCTCCTCCTCGC-T is Pathogenic according to our data. Variant chrX-154097608-TCTCCTCCTCGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 189770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154097608-TCTCCTCCTCGC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.47_57delGCGAGGAGGAG	p.Gly16GlufsTer22	frameshift_variant	Exon 1 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-114_-104delGCGAGGAGGAG		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.47_57delGCGAGGAGGAG	p.Gly16GlufsTer22	frameshift_variant	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.-114_-104delGCGAGGAGGAG		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 915109 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 280061

African (AFR) AF: 0.00 AC: 0 AN: 19731

American (AMR) AF: 0.00 AC: 0 AN: 19601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13525

East Asian (EAS) AF: 0.00 AC: 0 AN: 20815

South Asian (SAS) AF: 0.00 AC: 0 AN: 34534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3061

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 747012

Other (OTH) AF: 0.00 AC: 0 AN: 36238

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:5

Feb 18, 2024

Centre for Population Genomics, CPG

Significance: Pathogenic

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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in>=4 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_very strong). PMID: 15034579, 15689438 , 15857422, 17968969, 23810759 At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 15034579. This variant is absent from gnomAD (PM2_Supporting). -

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with MECP2-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability demonstrate X-linked recessive inheritance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by two clinical diagnostic laboratories (ClinVar). This variant is also present in RettBASE as associated with disease and has been reported in multiple individuals with atypical Rett syndrome, classic Rett syndrome or epilepsy with autism spectrum disorder (Rettsyndrome.org; PMIDs: 15689438, 23810759, 31139143). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 05, 2013

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

-

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MECP2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001110792.1, and corresponds to NM_004992.3:c.-114_-104del in the primary transcript. This sequence change creates a premature translational stop signal (p.Gly16Glufs*22) in the MECP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MECP2 are known to be pathogenic (PMID: 12180070). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 15857422, 16155192, 17968969, 22213695, 23810759). In at least one individual the variant was observed to be de novo. This variant is also known as c.38_48del11. ClinVar contains an entry for this variant (Variation ID: 189770). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs786205042; hg19: chrX-153363065;