rs267608475

chrX-154031415-A-GchrX-154031415-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001110792.2(MECP2):c.449T>C(p.Leu150Ser) 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L150F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.83

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 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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-154031414-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3024298.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.449T>C	p.Leu150Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.413T>C	p.Leu138Ser	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.449T>C	p.Leu150Ser	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.413T>C	p.Leu138Ser	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	curation	RettBASE	Dec 03, 2010	- -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 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 2.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score ‚> 0.75) (PP3). This variant is absent from gnomAD v.4.0.0 (PM2_Supporting). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.7	D;D;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Benign	0.15	T;T;D;D;.;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.95
MutPred		0.81		Loss of helix (P = 0.0093);.;Loss of helix (P = 0.0093);.;Loss of helix (P = 0.0093);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs267608475; hg19: chrX-153296866;