rs61754452

Positions:

• chrX-154032283-G-A
• chrX-154032283-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5_Strong PS4 PM2_Supporting PM1 PP4 PP3

This summary comes from the ClinGen Evidence Repository: The p.Pro101Ser variant has been observed in at least 4 other individuals with Rett syndrome (RettBASE, internal database) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10767337, 31439979) (PM5_Strong). The p.Pro101Ser variant in MECP2 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Pro101Ser variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 11269512) (PP4). In summary, the p.Pro101Ser variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM5_strong, PM2_supporting, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA270328/MONDO:0010726/016

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.47

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 13 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.337C>T	p.Pro113Ser	missense_variant	2/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.301C>T	p.Pro101Ser	missense_variant	3/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.337C>T	p.Pro113Ser	missense_variant	2/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.301C>T	p.Pro101Ser	missense_variant	3/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 24, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Pro101Ser variant has been observed in at least 4 other individuals with Rett syndrome (RettBASE, internal database) (PS4). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 10767337, 31439979) (PM5_Strong). The p.Pro101Ser variant in MECP2 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Pro101Ser variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 11269512) (PP4). In summary, the p.Pro101Ser variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS4, PM5_strong, PM2_supporting, PP3, PP4). -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Oct 12, 2023	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 likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant is absent from gnomAD (PM2_Supporting). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6, PMID: 11269512). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease (PS4_Moderate, RettBASE internal database). Computational prediction analysis tools suggests a deleterious impact (REVEL score >=0.75) (PP3). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 03, 2006	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D;D;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D;D;.;.;.;.;.
Sift4G	Benign	0.096	T;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.90
MutPred		0.94		Gain of phosphorylation at P101 (P = 0.0341);.;Gain of phosphorylation at P101 (P = 0.0341);.;Gain of phosphorylation at P101 (P = 0.0341);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.97

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: rs61754452; hg19: chrX-153297734;