rs1557135793

chrX-154030690-CG-CchrX-154030690-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001110792.2(MECP2):c.1173del(p.Val392CysfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P391P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.245

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 16 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 62 pathogenic variants in the truncated region.
• PP5: Variant X-154030690-CG-C is Pathogenic according to our data. Variant chrX-154030690-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536579.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.1173del	p.Val392CysfsTer29	frameshift_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1137del	p.Val380CysfsTer29	frameshift_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1173del	p.Val392CysfsTer29	frameshift_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1137del	p.Val380CysfsTer29	frameshift_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*509del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*509del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1087363 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 355521

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.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 25, 2023

Criteria applied: PVS1,PS4_MOD,PM2_SUP -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2017

For these reasons, this variant has been classified as Pathogenic. Many different deletions variants in this region of the MECP2 gene have been reported in affected individuals (PMID: 19914908, 16473305, Invitae) and therefore has been defined as a "deletion prone region" (PMID: 21878110, 14974082). This variant has not been reported in the literature in individuals with MECP2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MECP2 gene (p.Val380Cysfs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 107 amino acids of the MECP2 protein. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 15, 2019

This variant was identified as hemizygous -

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: rs1557135793; hg19: chrX-153296141;