rs61751440

chrX-154030918-T-CchrX-154030918-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):c.946A>G(p.Lys316Glu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K316N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.24

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 18 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, 5 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154030918-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 420031.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-154030918-T-C is Pathogenic according to our data. Variant chrX-154030918-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143742.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.946A>G	p.Lys316Glu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.910A>G	p.Lys304Glu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.946A>G	p.Lys316Glu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.910A>G	p.Lys304Glu	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The p.Lys304Glu variant in MECP2 (NM_004992.3) has been observed in at least 2 individuals with clinical features of Rett syndrome (PMID 16473305, internal database - GeneDx) (PS4_supporting). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 16077736, ClinVar, internal database - GeneDx, internal database - Invitae) (PM5_strong). The p.Lys304Glu variant in MECP2 is absent from gnomAD (PM2_supporting). MECP2 in vitro binding and transcription repression assays have shown that this variant impacts protein function (PMID 23770565) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Lys304Glu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM5_strong, PS3_supporting, PS4_supporting, PM2_supporting, PP3). -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Sep 25, 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 likely pathogenic. At least the following criteria are met: ≥2 different missense variants in the same codon have been classified as pathogenic (PM5_Strong). Computational prediction analysis tools suggests a deleterious impact (REVEL score >=0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). Has been observed in in at least 2 individuals with phenotypes consistent with MECP2-related disease (PS4_Supporting). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jan 21, 2008	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2019

Published functional studies demonstrate K304E impacts the binding ability of MECP2 (Lyst et al., 2013); Multiple pathogenic missense variants at this residue (p.K304Q and p.K304T) have been reported in association with Rett syndrome (Charman et al., 2005; Lindy et al., 2018); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28348241, 24970834, 16473305, 23770565) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.22	N;N
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.99	D;D
Vest4		0.64
MutPred		0.86		Loss of methylation at K304 (P = 0.0025);.;
MVP		1.0
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61751440; hg19: chrX-153296369;