rs1042870

chrX-154031051-G-AchrX-154031051-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):c.813C>T(p.Ala271=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,210,655 control chromosomes in the GnomAD database, including 1 homozygotes. There are 283 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A271A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., 33 hem., cov: 23)
  • Exomes 𝑓: 0.00068 (0 hom. 250 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-154031051-G-A is Benign according to our data. Variant chrX-154031051-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031051-G-A is described in Lovd as [Likely_benign]. Variant chrX-154031051-G-A is described in Lovd as [Pathogenic]. Variant chrX-154031051-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000807 (91/112715) while in subpopulation AMR AF= 0.00204 (22/10792). AF 95% confidence interval is 0.00138. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.813C>T	p.Ala271=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.777C>T	p.Ala259=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.813C>T	p.Ala271=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.777C>T	p.Ala259=	synonymous_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 91 AN: 112665 Hom.: 1 Cov.: 23 AF XY: 0.000948 AC XY: 33 AN XY: 34821

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000718

Gnomad FIN AF: 0.000322

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000601

Gnomad OTH AF: 0.00394

GnomAD3 exomes AF: 0.000476 AC: 87 AN: 182627 Hom.: 0 AF XY: 0.000401 AC XY: 27 AN XY: 67389

Gnomad AFR exome AF: 0.000693

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000683 AC: 750 AN: 1097940 Hom.: 0 Cov.: 35 AF XY: 0.000688 AC XY: 250 AN XY: 363330

Gnomad4 AFR exome AF: 0.000947

Gnomad4 AMR exome AF: 0.000568

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000265

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.000222

Gnomad4 NFE exome AF: 0.000761

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000807 AC: 91 AN: 112715 Hom.: 1 Cov.: 23 AF XY: 0.000946 AC XY: 33 AN XY: 34881

Gnomad4 AFR AF: 0.000869

Gnomad4 AMR AF: 0.00204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000720

Gnomad4 FIN AF: 0.000322

Gnomad4 NFE AF: 0.000601

Gnomad4 OTH AF: 0.00389

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000793

EpiCase AF: 0.000872

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 18, 2018	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2014	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	Dec 03, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Rett syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2015	- -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 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 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 3.0 (BA1). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.064
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1042870; hg19: chrX-153296502;