X-154030721-ATGGTGG-ATGG

Variant names:

• chrX-154030721-ATGG-A
• rs61752381
• NM_001110792.2:c.1140_1142delCCA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP3 BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. H380H) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 15 uncertain in NM_001110792.2
• BP3: Nonframeshift variant in repetitive region in NM_001110792.2
• BS2: High AC in GnomAdExome4 at 7 XL,Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1140_1142delCCA	p.His381del	disruptive_inframe_deletion	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1104_1106delCCA	p.His369del	disruptive_inframe_deletion	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.825_827delCCA	p.His276del	disruptive_inframe_deletion	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1140_1142delCCA	p.His381del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1104_1106delCCA	p.His369del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1104_1106delCCA	p.His369del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 178566 AF XY: 0.0000154

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26314

American (AMR) AF: 0.00 AC: 0 AN: 35078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3985

European-Non Finnish (NFE) AF: 0.00000833 AC: 7 AN: 840710

Other (OTH) AF: 0.00 AC: 0 AN: 45979

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

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

Feb 15, 2002

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Jun 30, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 14, 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: 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

Dec 30, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 06, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs61752381; hg19: chrX-153296172;