rs179363901

chrX-154097661-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP5_Very_Strong

The NM_001110792.2(MECP2):c.5C>T(p.Ala2Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.71

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 9 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant X-154097661-G-A is Pathogenic according to our data. Variant chrX-154097661-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154097661-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.5C>T	p.Ala2Val	missense_variant	1/3	ENST00000453960.7
MECP2	NM_004992.4	c.-156C>T		5_prime_UTR_variant	1/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.5C>T	p.Ala2Val	missense_variant	1/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.-156C>T		5_prime_UTR_variant	1/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 911162 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 283614

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Feb 18, 2024	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 3.0, 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 at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong). PMID 19034540, 19365833, ClinVar; [VCV000011845.5] At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID: 19365833 This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	-	- -
Likely pathogenic, no assertion criteria provided	research	RettBASE	Apr 26, 2016	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MECP2 function (PMID: 28973632). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 11845). This missense change has been observed in individual(s) with Rett syndrome (PMID: 19034540, 19365833, 23238081). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 2 of the MECP2 protein (p.Ala2Val). The MECP2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001110792.1, and corresponds to NM_004992.3:c.-156C>T in the primary transcript. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.0047	A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.35	N;.
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.070	T;D
Polyphen		0.0010	B;.
Vest4		0.48
MutPred		0.31		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.88
ClinPred		0.93	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.76

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: rs179363901; hg19: chrX-153363118;