rs267608388

chrX-154032241-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_001110792.2(MECP2):c.379C>T(p.Arg127Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000455 in 1,097,744 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000046 (0 hom. 4 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3 O:1
• Conservation: PhyloP100: 6.27

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.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001110792.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154032240-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2505626.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.379C>T	p.Arg127Cys	missense_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4	c.343C>T	p.Arg115Cys	missense_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.379C>T	p.Arg127Cys	missense_variant	2/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.343C>T	p.Arg115Cys	missense_variant	3/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097744 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	RettBASE	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2022	Observed as an apparently de novo variant in a female with classic Rett syndrome in published literature; however, another apparently de novo variant in MECP2 was also identified (Bunyan et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10577905, 22561697, 20631224, 21575601, 34426522, 21831886, 12843318, 32653844, 18652533) -

Rett syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 28, 2023

The p.Arg115Cys (NM_004992.4) in MECP2 occurs in the de novo state (biological parentage unconfirmed) in an individual with classic Rett syndrome; however, this individual was also heterozygous for a de novo truncating variant in MECP2 (PMID 18652533). The p.Arg115Cys variant (NM_004992.4) occurs in the well-characterized methyl-DNA binding (MDB) functional domain of MECP2 (PMID 21326358, 23770565) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg115Cys variant (NM_004992.4) in MECP2 is absent from gnomAD (PM2_supporting). The p.Arg115Cys variant (NM_004992.4) is observed in at least 2 unaffected individuals (internal databases) (BS2). In summary, the p.Arg115Cys variant in MECP2 (NM_004992.4) is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, BS2). -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 17, 2023

This missense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 18652533). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 143541). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 115 of the MECP2 protein (p.Arg115Cys). -

History of neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2016

The p.R115C variant (also known as c.343C>T), located in coding exon 2 of the MECP2 gene, results from a C to T substitution at nucleotide position 343. The arginine at codon 115 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified asde novo in a female individual with classic Rettsyndrome who also carrieda de novoframeshiftmutation in MECP2. The phase of the two alterations was not confirmed and there was no evidence of skewed x-inactivation (Bunyan DJ, Genet. Test. 2008 Sep; 12(3):373-5).This variant was previously reported in the SNPDatabase as rs267608388, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases.This amino acid position is highly 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,theclinical significance of this variantremains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;T;D;D;T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.20	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D;D;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.80
MutPred		0.81		Loss of MoRF binding (P = 0.0068);.;Loss of MoRF binding (P = 0.0068);.;Loss of MoRF binding (P = 0.0068);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.75
gMVP		0.96

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: rs267608388; hg19: chrX-153297692;