rs786205042

Positions:

• chrX-154097608-TCTCCTCCTCGC-T
• chrX-154097608-TCTCCTCCTCGC-TCTCCTCCTCGCCTCCTCCTCGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):​c.47_57delGCGAGGAGGAG​(p.Gly16fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar 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]

MECP2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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. Fraction of 0.969 CDS is truncated, and there are 1 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/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.47_57delGCGAGGAGGAG	p.Gly16fs	frameshift_variant	1/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-114_-104delGCGAGGAGGAG		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	c.47_57delGCGAGGAGGAG	p.Gly16fs	frameshift_variant	1/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.-114_-104delGCGAGGAGGAG		5_prime_UTR_variant	1/4	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Feb 18, 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 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). -
Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	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 -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189770). This variant is also known as c.38_48del11. 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 not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205042; hg19: chrX-153363065;