rs61751449

Positions:

• chrX-154030864-G-A
• chrX-154030864-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.1000C>T​(p.Pro334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P334L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.86

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 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154030863-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 143754.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant X-154030864-G-A is Pathogenic according to our data. Variant chrX-154030864-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1000C>T	p.Pro334Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.964C>T	p.Pro322Ser	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1000C>T	p.Pro334Ser	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.964C>T	p.Pro322Ser	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

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	Aug 14, 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: This variant is absent from gnomAD (PM2_Supporting). It has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease (PS4_Moderate, PMID: 16966553, PMID: 30573328, PMID: 32370253, PMID: 30536762). Another missense variant in the same codon has been classified as pathogenic for Rett syndrome by the ClinGen Rett and Angelman-like Disorders Expert Panel (PM5, CA270591). -
Likely pathogenic, no assertion criteria provided	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 06, 2020	- -
Pathogenic, no assertion criteria provided	research	RettBASE	Apr 26, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2018

- -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 12, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D
Sift4G	Benign	0.17	T
Vest4		0.43
MVP		0.98
ClinPred		0.78	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61751449; hg19: chrX-153296315;