rs1557134946

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 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. Variant has been reported in ClinVar 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

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

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 10, 2002

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557134946; hg19: chrX-153295878;