rs267608612

chrX-154030630-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):c.1233_1234insC(p.Thr412HisfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P411P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.44

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 32 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154030630-T-TG is Pathogenic according to our data. Variant chrX-154030630-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1233_1234insC	p.Thr412HisfsTer5	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1197_1198insC	p.Thr400HisfsTer5	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1197_1198insC	p.Thr400HisfsTer5	frameshift_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1233_1234insC	p.Thr412HisfsTer5	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*569_*570insC		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*569_*570insC		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 20

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	curation	RettBASE	Feb 18, 2008	- -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Oct 11, 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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 14, 2021

The MECP2 c.1197dupC; p.Thr400HisfsTer5 variant (rs267608612), also known as c.1194insC is reported in the literature in multiple individuals affected with Rett syndrome (Fukuda 2005, RettBASE). This variant is also reported in ClinVar (Variation ID: 143432). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MECP2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of five amino acid residues not usually present. Based on available information, this variant is considered to be likely pathogenic. References: Fukuda T et al. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005 Apr;27(3):211-7. PMID: 15737703. Link to RettBASE- RettSyndrome.org Variation Database: mecp2.chw.edu.au -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608612; hg19: chrX-153296081;