rs61751439

Positions:

• chrX-154030919-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001110792.2(MECP2):​c.945C>G​(p.Ile315Met) variant causes a missense change involving the alteration of a non-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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: 1.66

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant X-154030919-G-C is Pathogenic according to our data. Variant chrX-154030919-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.945C>G	p.Ile315Met	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.909C>G	p.Ile303Met	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.945C>G	p.Ile315Met	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.909C>G	p.Ile303Met	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2015	- -
Likely pathogenic, 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 likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Transcriptional repression domain (TRD) of MECP2 (PM1). Another missense variant in the same codon has been classified as pathogenic (PM5). This variant has been identified as a de novo occurrence in an individual with MECP2-related condition without confirmation of paternity and maternity (PM6). This variant is absent from gnomAD (PM2_Supporting). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 11, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with MECP2-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Rett syndrome is inherited in an X-linked dominant pattern, while MECP2-related encephalopathy and intellectual disability demonstrate X-linked recessive inheritance (PMID: 20301670). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative amino acid changes at the same codon, p.(Ile315Ser) and p.(Ile315Val), have been previously reported (ClinVar, PMID: 16473305). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in two de novo individuals with MECP2-related features and has been reported without classification and as a VUS (PMIDs: 22277191, 15173251). It has also been reported as VUS in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) [LAB ID]. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Sep 27, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.56	N;N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.092	T;T
Polyphen		0.99	D;D
Vest4		0.57
MutPred		0.72		Loss of methylation at K304 (P = 0.0339);.;
MVP		0.99
ClinPred		0.94	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.98

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: rs61751439; hg19: chrX-153296370; COSMIC: COSV57654475; COSMIC: COSV57654475;