rs786205045

Positions:

• chrX-154097618-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001110792.2(MECP2):​c.48C>T​(p.Gly16=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 924,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.52

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-154097618-G-A is Pathogenic according to our data. Variant chrX-154097618-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154097618-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.48C>T	p.Gly16=	synonymous_variant	1/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-113C>T		5_prime_UTR_variant	1/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.48C>T	p.Gly16=	synonymous_variant	1/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.-113C>T		5_prime_UTR_variant	1/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000108 AC: 1 AN: 924253 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 284217

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: 0.00

Gnomad4 NFE exome AF: 0.00000133

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 03, 2024	- -
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 pathogenic. At least the following criteria are met: This variant has been identified as a de novo occurrence in an individual with Rett syndrome with confirmed parental relationships (PS2, PMID: 23866855). Well-established in vitro or in vivo functional studies strongly supportive of a damaging effect on the protein function (PS3, PMID: 23866855). At least one patient with this variant has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PP4, PMID: 23866855). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.48C>T (p.G16G) alteration is located in exon 1 (coding exon 1) of the MECP2 gene. This alteration consists of a C to T substitution at nucleotide position 48. This nucleotide substitution does not change the amino acid at codon 16. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one female with features consistent with Rett syndrome (Sheikh, 2013). This nucleotide position is highly conserved in available vertebrate species. Functional analysis demonstrated that this alteration causes abnormal splicing (Sheikh, 2013). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2018

The c.48 C>T variant in the MECP2 gene was reported previously as an assumed de novo variant in a female with classic Rett syndrome and has also been detected as a confirmed de novo variant in a patient tested at GeneDx (Sheikh et al., 2013). The c.48 C>T variant is a silent substitution that alters a conserved position in the MECP2_e1 transcript. In silico models predict it creates a cryptic splice donor site, leading to abnormal gene splicing. Sequencing of cDNA from lymphocytes of a patient heterozygous for c.48 C>T confirmed this variant results in alternative splicing that introduces a premature stop codon, and quantitative mRNA analysis detected both the mutant transcript and reduced levels of the wildtype MECP2_e1 transcript compared to healthy controls (Sheikh et al., 2013). The c.48 C>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.48 C>T as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 2
DS_DL_spliceai		0.22		Position offset: -14

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205045; hg19: chrX-153363075;