rs267608411

Positions:

• chrX-154032563-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.63-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 3.40

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154032563-G-C is Pathogenic according to our data. Variant chrX-154032563-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032563-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.63-6C>G		splice_region_variant, intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.27-6C>G		splice_region_variant, intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.63-6C>G		splice_region_variant, intron_variant		1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.27-6C>G		splice_region_variant, intron_variant		1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 16, 2024	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 likely pathogenic. At least the following criteria are met: Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3). PMID: 11241840 This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 11241840 This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 11, 2015	- -
Pathogenic, no assertion criteria provided	curation	RettBASE	Sep 05, 2002	- -

not provided Other:1

not provided, flagged submission

literature only

RettBASE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	26
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1
DS_AL_spliceai		0.64		Position offset: -6

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608411; hg19: chrX-153298014;