X-154097642-CGCGGCGGCG-CGCG

Variant names:

• chrX-154097642-CGCGGCG-C
• rs398123566
• NM_001110792.2:c.18_23delCGCCGC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Strong BS2

The NM_001110792.2(MECP2):​c.18_23delCGCCGC​(p.Ala7_Ala8del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000381 in 1,024,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.000036 (0 hom. 4 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 4.00

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 Benign. Variant got -8 ACMG points.

• BP6: Variant X-154097642-CGCGGCG-C is Benign according to our data. Variant chrX-154097642-CGCGGCG-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 156657.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chrX-154097642-CGCGGCG-C is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.18_23delCGCCGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-143_-138delCGCCGC		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.18_23delCGCCGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.-143_-138delCGCCGC		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0000563 AC: 6 AN: 106552 Hom.: 0 Cov.: 21 AF XY: 0.0000994 AC XY: 3 AN XY: 30188

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000307

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000197

Gnomad OTH AF: 0.000695

GnomAD4 exome AF: 0.0000360 AC: 33 AN: 917924 Hom.: 0 AF XY: 0.0000140 AC XY: 4 AN XY: 284702

Gnomad4 AFR exome AF: 0.000202

Gnomad4 AMR exome AF: 0.0000585

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000315

Gnomad4 FIN exome AF: 0.0000463

Gnomad4 NFE exome AF: 0.0000332

Gnomad4 OTH exome AF: 0.0000271

GnomAD4 genome AF: 0.0000563 AC: 6 AN: 106585 Hom.: 0 Cov.: 21 AF XY: 0.0000992 AC XY: 3 AN XY: 30233

Gnomad4 AFR AF: 0.000101

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000308

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000197

Gnomad4 OTH AF: 0.000686

Bravo AF: 0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Benign:2

Apr 18, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The highest population minor allele frequency of the c.-143_-138del variant in MECP2 (NM_004992.4) in gnomAD v4.0 is 0.0001412 in the African/African American population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). Larger deletions encompassing this region (c.-143_-138del) have been observed in an unaffected mother and father (Invitae internal database) (BP3). This variant has been observed in an individual with neurodevelopment disorder (PMID 1717659) (not sufficient for PS4_supporting). In summary, the c.-143_-138del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP3). -

Jan 16, 2024

Centre for Population Genomics, CPG

Significance: Benign

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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

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

Nov 01, 2007

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

MECP2-related disorder Uncertain:1

Mar 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MECP2 c.18_23del6 variant is predicted to result in an in-frame deletion (p.Ala7_Ala8del). This variant has been reported in an individual with intellectual disability (Harvey et al. 2007. PubMed ID: 17171659). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Oct 27, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs398123566; hg19: chrX-153363099;