rs1557150846

chrX-154097608-T-TCTCCTCCTCGCCTCCTC

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.57_58insGAGGAGGCGAGGAGGAG(p.Arg20GlufsTer30) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.73

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 367 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154097608-T-TCTCCTCCTCGCCTCCTC is Pathogenic according to our data. Variant chrX-154097608-T-TCTCCTCCTCGCCTCCTC is described in ClinVar as [Pathogenic]. Clinvar id is 406153.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.57_58insGAGGAGGCGAGGAGGAG	p.Arg20GlufsTer30	frameshift_variant	1/3	ENST00000453960.7
MECP2	NM_004992.4	c.-104_-103insGAGGAGGCGAGGAGGAG		5_prime_UTR_variant	1/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.57_58insGAGGAGGCGAGGAGGAG	p.Arg20GlufsTer30	frameshift_variant	1/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.-104_-103insGAGGAGGCGAGGAGGAG		5_prime_UTR_variant	1/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MECP2 are known to be pathogenic (PMID: 12180070). This variant has been reported to be de novo in an individual affected with Rett syndrome (PMID: 27171548). This variant is not present in population databases (ExAC no frequency). This sequence change inserts 17 nucleotides in exon 1 of the MECP2 mRNA (NM_001110792.1:c.41_57dup), causing a frameshift at codon 20. This creates a premature translational stop signal (p.Arg20Glufs*30) and is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2020

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27171548) -

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: rs1557150846; hg19: chrX-153363065;