chrX-154031445-T-G

Position:

• chrX-154031445-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):​c.419A>C​(p.Gln140Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely 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:3 U:1
• Conservation: PhyloP100: 5.73

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant X-154031445-T-G is Pathogenic according to our data. Variant chrX-154031445-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.419A>C	p.Gln140Pro	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.383A>C	p.Gln128Pro	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.419A>C	p.Gln140Pro	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.383A>C	p.Gln128Pro	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	curation	RettBASE	Nov 15, 2007	- -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Nov 09, 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 has been identified as a de novo occurrence in >=2 individuals with Rett syndrome without confirmation of paternity and maternity (PM6_strong, PMID: 12966523, 15875198). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score >= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 128 of the MECP2 protein (p.Gln128Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rett Syndrome (PMID: 12966523, 15875198). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143554). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2017

The p.Q128P variant (also known as c.383A>C), located in coding exon 3 of the MECP2 gene, results from an A to C substitution at nucleotide position 383. The glutamine at codon 128 is replaced by proline, an amino acid with similar properties. This alteration has been detected as a de novo occurrence twice: once in a female with later onset regression variant Rett syndrome and once in a female with atypical Rett syndrome without a regression period (Smeets E et al. Am. J. Med. Genet. A, 2003 Oct;122A:227-33; Giampietro PF et al. Childs Nerv Syst, 2006 Mar;22:320-4). In addition, this alteration is located in the Methyl-CpG DNA binding domain and is directly involved in binding interactions (Ramage R et al. Biochem. J., 1994 Apr;299 ( Pt 1):151-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;T;D;D;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	D;D;.;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D;D;.;.;.;.;.
Sift4G	Benign	0.065	T;D;D;D;.;T;D
Polyphen		0.88	P;P;.;.;.;.;.
Vest4		0.62
MutPred		0.77		Loss of MoRF binding (P = 0.0605);.;Loss of MoRF binding (P = 0.0605);.;Loss of MoRF binding (P = 0.0605);.;.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61748383; hg19: chrX-153296896;