NM_001110792.2:c.1197_1436del

Variant names:

• chrX-154030427-TGGCATGGAGGATGAAACAATGTCTTTGCGCTCTCCCTCCCCTCGGTGTTTGTACTTTTCTGCGGCCGTGGCGGCGGTGGCAACCGCGGGCTGAGTCTTAGCTGGCTCCTTGGGGCAGCCGTCGCTCTCCAGTGAGCCTCCTCTGGGCATCTTCTCCTCTTTGCAGACGCTGCTGCTCAAGTCCTGGGGCTCAGGGGGGCTGGTGGGGTCCTCGGAGCTCTCGGGCTCAGGTGGAGGTGGG-T
• rs1557134946
• NM_001110792.2:c.1197_1436del

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP3

The NM_001110792.2(MECP2):​c.1197_1436del​(p.Pro400_Pro479del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. P399null) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 7.74
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 12 uncertain in NM_001110792.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1197_1436del	p.Pro400_Pro479del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1161_1400del	p.Pro388_Pro467del	disruptive_inframe_deletion	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1197_1436del	p.Pro400_Pro479del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1161_1400del	p.Pro388_Pro467del	disruptive_inframe_deletion	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1 Uncertain:1

Apr 10, 2002

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rett syndrome Uncertain:2

Mar 13, 2024

Centre for Population Genomics, CPG

Significance: Uncertain significance

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 a variant of uncertain significance. At least the following criteria are met: Protein length changes due to in-frame deletions/insertions in a non-repeat region (PM4). Co-segregation with disease in multiple affected family members in at least 2 informative meiosis (PP1). PMID: 11807877 This variant is absent from gnomAD (PM2_Supporting). -

Oct 13, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The p.Pro400_Pro479del variant in MECP2 (NM_004992.3) causes an in-frame deletion of 80 amino acids, including a deletion of 62 amino acids in a non-repeat region of MECP2. This results in a deletion of greater than 10% of the total protein length (PM4_strong). The variant has been reported to segregate with mild non-syndromic intellectual disability in males in two informative meioses (PMID 11807877) (PP1). In summary, the p.Pro388_Pro467del variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM4_strong, PP1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=2/198	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs1557134946; hg19: chrX-153295878;