rs267608332

Variant names:

• chrX-154030661-AGGTGGGG-A
• rs267608332
• NM_001110792.2:c.1196_1202delCCCCACC

Your query was ambiguous. Multiple possible variants found:

• chrX-154030661-AGGTGGGG-A
• chrX-154030661-AGGTGGGG-AG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001110792.2(MECP2):​c.1196_1202delCCCCACC​(p.Pro399LeufsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 552,051 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.000039 (0 hom. 4 hem.)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.20
• 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: Pathogenic. The variant received 12 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 137 pathogenic variants in the truncated region.
• PP5: Variant X-154030661-AGGTGGGG-A is Pathogenic according to our data. Variant chrX-154030661-AGGTGGGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 143384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 21 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1196_1202delCCCCACC	p.Pro399LeufsTer20	frameshift_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1160_1166delCCCCACC	p.Pro387LeufsTer20	frameshift_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1196_1202delCCCCACC	p.Pro399LeufsTer20	frameshift_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1160_1166delCCCCACC	p.Pro387LeufsTer20	frameshift_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0000609 AC: 1 AN: 16414 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000115

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000755 AC: 1 AN: 132529 AF XY: 0.0000204

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: 0.0000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000392 AC: 21 AN: 535637 Hom.: 0 AF XY: 0.0000255 AC XY: 4 AN XY: 156659

African (AFR) AF: 0.00 AC: 0 AN: 13489

American (AMR) AF: 0.00 AC: 0 AN: 17484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7694

East Asian (EAS) AF: 0.00 AC: 0 AN: 7836

South Asian (SAS) AF: 0.00 AC: 0 AN: 22278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13189

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1775

European-Non Finnish (NFE) AF: 0.0000462 AC: 20 AN: 432938

Other (OTH) AF: 0.0000528 AC: 1 AN: 18954

GnomAD4 genome AF: 0.0000609 AC: 1 AN: 16414 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4652

African (AFR) AF: 0.00 AC: 0 AN: 3899

American (AMR) AF: 0.00 AC: 0 AN: 1398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 448

East Asian (EAS) AF: 0.00 AC: 0 AN: 763

South Asian (SAS) AF: 0.00 AC: 0 AN: 374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.000115 AC: 1 AN: 8681

Other (OTH) AF: 0.00 AC: 0 AN: 209

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:3

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift c.1196_1202del(p.Pro399LeufsTer20) variant in MECP2 gene has been reported previously in individual(s) affected with Rett syndrome (Hadzsiev K, et. al., 2011; Kárteszi J, et. al., 2004). The p.Pro399LeufsTer20 variant has been reported with allele frequency of 0.0008% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Proline 399, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Pro399LeufsTer20. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Aug 14, 2023

Centre for Population Genomics, CPG

Significance: Pathogenic

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 2.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant is absent from the NHLBI exome sequencing project (PM2_Supporting). It has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease (PS4_Moderate, RettBase internal database, PMID: 20031356, PMID: 21160487, PMID: 15389714). -

Nov 01, 2011

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Pathogenic:1

Oct 14, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1160_1166delCCCCACC pathogenic variant in the MECP2 gene has been reported previously in association with Rett syndrome (Hadzsiev et al., 2011; Karteszi et al., 2004; Monnerat et al., 2010). The deletion causes a frameshift starting with codon Proline 387, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 20 of the new reading frame, denoted p.P387LfsX20. The c.1160_1166delCCCCACC variant is predicted to cause loss of normal protein function through protein truncation, as the last 100 amino acids are replaced with 19 incorrect ones. Additionally, this variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267608332; hg19: chrX-153296112;