rs587783137

chrX-154031260-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_001110792.2(MECP2):c.604C>T(p.Arg202Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000728 in 1,098,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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. R202H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 4.23

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 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154031259-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548706.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.604C>T	p.Arg202Cys	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.568C>T	p.Arg190Cys	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.604C>T	p.Arg202Cys	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.568C>T	p.Arg190Cys	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000218 AC: 4 AN: 183282 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098224 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 2 AN XY: 363580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000712

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 31, 2021	The p.Arg190Cys (NM_004992.3) variant is observed in at least 1 unaffected adult individual (GeneDx internal database) (BS2_supporting). The p.Arg190Cys variant in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with schizophrenia (PMID 24776741) (PS2 - not met as patient was not described to have features of Rett syndrome). A missense variant (p.Arg190His) has been previously identified within this codon which may indicate that this residue is critical to the function of the protein; however, this variant is not currently classified as pathogenic by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (PM5- not met). In summary, the p.Arg190Cys variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2_supporting). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it once in our laboratory in a 7-year-old female with global delays, regression, autism, hypotonia, epilepsy, aggressive behavior. Mom did not carry the variant, father not tested -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

This sequence change replaces arginine with cysteine at codon 190 of the MECP2 protein (p.Arg190Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587783137, ExAC 0.002%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with schizophrenia (PMID: 24776741). ClinVar contains an entry for this variant (Variation ID: 156667). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2020

De novo variant with confirmed parentage in a patient with schizophrenia in published literature, using alternate nomenclature R202C (McCarthy et al., 2014); Published functional studies suggest that R190C is damaging to MECP2 function in vitro and in cell lines (Sheikh et al., 2018); This variant is associated with the following publications: (PMID: 24776741, 29431277, 29655203) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D;D;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.56
MutPred		0.32		Loss of methylation at R190 (P = 0.0038);.;Loss of methylation at R190 (P = 0.0038);.;
MVP		0.98
ClinPred		0.82	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.83

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: rs587783137; hg19: chrX-153296711;