rs179363901

Variant names:

• chrX-154097661-G-A
• rs179363901
• NM_001110792.2:c.5C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154097661-G-A
• chrX-154097661-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.5C>T​(p.Ala2Val) 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: 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:6
• 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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-156C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.-156C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:4

Apr 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 18, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Apr 26, 2016

RettBASE

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the MECP2 protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. ClinVar contains an entry for this variant (Variation ID: 11845). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects MECP2 function (PMID: 28973632). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, including impaired methionine excision and increased proteasomal degradation rate (PMID: 28973632); In silico analysis supports that this missense variant does not alter protein structure/function; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 23238081, 19365833, 27929079, 19034540, 32472557, 33057194, 35982159, 28973632) -

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
DEOGEN2	Benign	0.062	.;T
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
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;