rs61750251

chrX-154030988-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001110792.2(MECP2):c.876C>T(p.Ala292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,209,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00035 (0 hom. 120 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -2.11

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-154030988-G-A is Benign according to our data. Variant chrX-154030988-G-A is described in ClinVar as [Benign]. Clinvar id is 138190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030988-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.11 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.876C>T	p.Ala292=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.840C>T	p.Ala280=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.876C>T	p.Ala292=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.840C>T	p.Ala280=	synonymous_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 26 AN: 111991 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34139

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000245

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.000254 AC: 46 AN: 181066 Hom.: 0 AF XY: 0.000149 AC XY: 10 AN XY: 67086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000726

Gnomad SAS exome AF: 0.000314

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000448

GnomAD4 exome AF: 0.000348 AC: 382 AN: 1097907 Hom.: 0 Cov.: 35 AF XY: 0.000330 AC XY: 120 AN XY: 363367

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000369

Gnomad4 FIN exome AF: 0.000373

Gnomad4 NFE exome AF: 0.000394

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000232 AC: 26 AN: 112043 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34201

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.000280

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.000245

Gnomad4 OTH AF: 0.000654

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000283

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	curation	RettBASE	Mar 29, 2011	- -

Rett syndrome Benign:2

Benign, 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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	May 10, 2022	The allele frequency of the p.Ala280= variant in MECP2 (NM_004992) is 0.034% in European (Non-Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala280= variant is observed in at least 2 unaffected individuals (PMID 11469283, PMID 20479760) (BS2). In summary the p.Ala280= variant in MECP2 is classified as Benign for Rett syndrome disorder based on the ACMG/AMP criteria (BA1, BS2). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

MECP2: BP4, BP7 -

MECP2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.0060
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs61750251; hg19: chrX-153296439;