X-154030721-ATGGTGG-ATGG

Position:

• chrX-154030721-ATGGTGG-ATGG

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001110792.2(MECP2):​c.1140_1142delCCA​(p.His381del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,095,703 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.41

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 Likely_benign. Variant got -1 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1140_1142delCCA	p.His381del	disruptive_inframe_deletion	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1104_1106delCCA	p.His369del	disruptive_inframe_deletion	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1140_1142delCCA	p.His381del	disruptive_inframe_deletion	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1104_1106delCCA	p.His369del	disruptive_inframe_deletion	4/4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000407218	c.*476_*478delCCA		3_prime_UTR_variant	4/4	5		ENSP00000384865.2
MECP2	ENST00000628176	c.*476_*478delCCA		3_prime_UTR_variant	5/5	3		ENSP00000486978.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000112 AC: 2 AN: 178566 Hom.: 0 AF XY: 0.0000154 AC XY: 1 AN XY: 64890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000252

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1095703 Hom.: 0 AF XY: 0.00000553 AC XY: 2 AN XY: 361509

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: 0.00000833

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 15, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 30, 2015	- -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 14, 2024	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: This variant is absent from gnomAD (PM2_Supporting). Protein length changes of < 3 amino acid residues due to in-frame deletions/insertions in a non-repeat region (PM4_Supporting). -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2021

This variant, c.1104_1106del, results in the deletion of 1 amino acid(s) of the MECP2 protein (p.His372del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs61752381, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with MECP2-related conditions (PMID: 23696494). ClinVar contains an entry for this variant (Variation ID: 143331). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 06, 2017

The c.1104_1106delCCA variant has been reported previously as a de novo change in an individual with Rett syndrome who had another de novo variant in the MECP2 gene (Chapleau et al. (2013). The c.1104_1106delCCA variant is observed in 2/78036 (0.003%) alleles from individuals of European background, including one hemizygous individual in large population cohorts (Lek et al., 2016). The c.1104_1106delCCA variant results in an in-frame deletion of a single Histidine residue, denoted p.His372del. This substitution occurs at a position that is conserved in mammals. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

MECP2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

The MECP2 c.1104_1106delCCA variant is predicted to result in an in-frame deletion (p.His372del). The p.His372del variant has been reported in a female patient with Rett syndrome as part of a complex de novo allele (Chapleau et al. 2013. PubMed ID: 23696494). However, the relevance of the p.His372del variant in this patient is unclear due to the presence of a downstream frameshift (c.1157_1197del41, p.Leu386Hisfs*4) on the same allele expected to lead to a loss of function. This variant is reported in 0.0025% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one hemizygous individual. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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: rs61752381; hg19: chrX-153296172;