NM_001110792.2:c.414-3_419delCAGTCCCCA

Variant names:

• chrX-154031444-CTGGGGACTG-C
• rs267608466
• NM_001110792.2:c.414-3_419delCAGTCCCCA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001110792.2(MECP2):​c.414-3_419delCAGTCCCCA​(p.Asn138_Gln140delinsLys) variant causes a splice acceptor, disruptive inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 splice_acceptor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.46

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates 0.7234468937875751 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031444-CTGGGGACTG-C is Pathogenic according to our data. Variant chrX-154031444-CTGGGGACTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 156069.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154031444-CTGGGGACTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.414-3_419delCAGTCCCCA	p.Asn138_Gln140delinsLys	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.378-3_383delCAGTCCCCA	p.Asn126_Gln128delinsLys	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_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.414-3_419delCAGTCCCCA	p.Asn138_Gln140delinsLys	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.378-3_383delCAGTCCCCA	p.Asn126_Gln128delinsLys	splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2

Nov 10, 2008

RettBASE

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Mar 15, 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 an individual with a MECP2-related condition without confirmation of paternity and maternity (PM6). PMID 18477000. This variant is absent from gnomAD (PM2_Supporting). -

not provided Other:1

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

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: rs267608466; hg19: chrX-153296895;