rs267608640

Variant names:

• chrX-154030370-GCTAA-G
• rs267608640
• NM_001110792.2:c.1490_1493delTTAG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP4 PM6_Strong PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Val485fs (NM_004992) variant in MECP2 is predicted to cause a frameshift that results in a read-through of the stop codon (PVS1). The p.Val485fs variant in MECP2 has been reported as de novo occurrence in at least two individuals (biological parentage unconfirmed) with Rett Syndrome (PMID 11402105, Clinvar Variation ID: 143485) (PM6_strong). The p.Val485fs variant has been observed in at least 3 other individuals with Rett Syndrome (PMID 11402105, PMID 16473305, ClinVar) (PS4_moderate). The p.Val485fs variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Val485fs variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett Syndrome (PMID 11402105) (PP4). In summary the p.Val485fs variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA273848/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.23

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: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1490_1493delTTAG	p.Val497AlafsTer26	frameshift_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1454_1457delTTAG	p.Val485AlafsTer26	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.1490_1493delTTAG	p.Val497AlafsTer26	frameshift_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1454_1457delTTAG	p.Val485AlafsTer26	frameshift_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*826_*829delTTAG		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000486978.1
MECP2	ENST00000407218.5	c.*826_*829delTTAG		downstream_gene_variant		5		ENSP00000384865.2

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Jan 10, 2024

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 3.0, 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 has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). (PMID 11402105, Clinvar Variation ID: 143485) Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). (PubMed: 11402105‚ 16473305 , ClinVar 143485) This variant is absent from gnomAD (PM2_Supporting). -

May 10, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Val485fs (NM_004992) variant in MECP2 is predicted to cause a frameshift that results in a read-through of the stop codon (PVS1). The p.Val485fs variant in MECP2 has been reported as de novo occurrence in at least two individuals (biological parentage unconfirmed) with Rett Syndrome (PMID 11402105, Clinvar Variation ID: 143485) (PM6_strong). The p.Val485fs variant has been observed in at least 3 other individuals with Rett Syndrome (PMID 11402105, PMID 16473305, ClinVar) (PS4_moderate). The p.Val485fs variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Val485fs variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett Syndrome (PMID 11402105) (PP4). In summary the p.Val485fs variant in MECP2 is classified as Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). -

Jan 21, 2008

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Feb 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the MECP2 protein. Other variant(s) that result in a similarly extended protein product (p.Ser486Ilefs*27) have been observed in individuals with MECP2-related disease (PMID: 20108430). This suggests that these extensions may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 143485). This frameshift has been observed in individual(s) with clinical features of MECP2-related conditions (PMID: 11402105, 16473305; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the MECP2 gene (p.Val485Alafs*26). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the MECP2 protein and extend the protein by 23 additional amino acid residues. -

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: rs267608640; hg19: chrX-153295821;