rs61748403

chrX-154031376-T-C

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.488A>G(p.Asp163Gly) 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. D163Y) 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:2
• Conservation: PhyloP100: 7.60

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 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-154031377-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 444834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant X-154031376-T-C is Pathogenic according to our data. Variant chrX-154031376-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143578.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154031376-T-C is described in Lovd as [Likely_pathogenic]. Variant chrX-154031376-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.488A>G	p.Asp163Gly	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.452A>G	p.Asp151Gly	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.488A>G	p.Asp163Gly	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.452A>G	p.Asp151Gly	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 13, 2023	The p.Asp151Gly variant in MECP2 (NM_004992.3) has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID 15173251) (PP4). The p.Asp151Gly variant has been observed in at least 3 other individuals with atypical Rett syndrome or clinical features of Rett syndrome (PMID 15173251, 32472557, internal database - University of Chicago, internal database - Invitae) (PS4_Moderate). The p.Asp151Gly variant occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). The p.Asp151Gly variant in MECP2 is absent from gnomAD (PM2_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.Asp151Gly variant in MECP2 is classified as Likely Pathogenic based on the ACMG/AMP criteria (PS4_moderate, PM1, PM2_supporting, PP3, PP4). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 10, 2016	- -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jan 21, 2008	- -
Likely 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 to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0 , this variant is classified as Likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

- -

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	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	2.0	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D;D;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D;D;.;.;.
Sift4G	Uncertain	0.018	D;T;.;T;D
Polyphen		0.97	D;D;.;.;.
Vest4		0.74
MutPred		0.83		Loss of stability (P = 0.0618);.;Loss of stability (P = 0.0618);.;.;
MVP		1.0
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61748403; hg19: chrX-153296827;