rs61753968

chrX-154030578-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001110792.2(MECP2):c.1286A>T(p.Lys429Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000906 in 110,435 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. K429K) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000091 (0 hom., 1 hem., cov: 22)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:1
• Conservation: PhyloP100: 2.29

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1744568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1286A>T	p.Lys429Met	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1250A>T	p.Lys417Met	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1286A>T	p.Lys429Met	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1250A>T	p.Lys417Met	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000628176.2	c.*622A>T		3_prime_UTR_variant	5/5	3
MECP2	ENST00000407218.5			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000906 AC: 1 AN: 110435 Hom.: 0 Cov.: 22 AF XY: 0.0000306 AC XY: 1 AN XY: 32637

Gnomad AFR AF: 0.0000330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000906 AC: 1 AN: 110435 Hom.: 0 Cov.: 22 AF XY: 0.0000306 AC XY: 1 AN XY: 32637

Gnomad4 AFR AF: 0.0000330

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Uncertain:2

Uncertain significance, no assertion criteria provided	curation	RettBASE	Sep 26, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 417 of the MECP2 protein (p.Lys417Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MECP2-related condition (PMID: 16832102). ClinVar contains an entry for this variant (Variation ID: 143450). 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 not expected to disrupt MECP2 protein function. 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. -

Rett syndrome Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The p.Lys417Met variant in MECP2 (NM_004992.3) is observed in at least 3 unaffected individuals (PMID 16832102; internal database - GeneDx) (BS2). The p.Lys417Met variant in MECP2 has been reported in a male with early onset encephalopathy (PMID 16832102). The p.Lys417Met variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Lys417Met variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BS2, PM2_supporting). -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 14, 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 a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting). PMID: 16832102 This variant is absent from gnomAD (PM2_Supporting). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported as a maternally inherited variant in a male with progressive encephalopathy. Although the authors note that the mother's X-inactivation pattern in peripheral blood lymphocytes appears random, clinical features of the mother were not provided (Kankirawatana et al., 2006).; This variant is associated with the following publications: (PMID: 22497713, 17351020, 19168818, 16832102, 19559301) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.34	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.0070	B;B
Vest4		0.18
MutPred		0.16		Loss of ubiquitination at K417 (P = 0.0011);.;
MVP		0.99
ClinPred		0.36	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.23
gMVP		0.36

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: rs61753968; hg19: chrX-153296029; COSMIC: COSV57654727; COSMIC: COSV57654727;