rs61754439

chrX-154032374-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001110792.2(MECP2):c.246C>T(p.Ser82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,211,438 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 35 hem., cov: 24)
  • Exomes 𝑓: 0.00025 (0 hom. 86 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.96

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-154032374-G-A is Benign according to our data. Variant chrX-154032374-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032374-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00109 (124/113349) while in subpopulation AFR AF= 0.00322 (101/31341). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.246C>T	p.Ser82=	synonymous_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4	c.210C>T	p.Ser70=	synonymous_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.246C>T	p.Ser82=	synonymous_variant	2/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.210C>T	p.Ser70=	synonymous_variant	3/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 120 AN: 113296 Hom.: 0 Cov.: 24 AF XY: 0.000903 AC XY: 32 AN XY: 35436

Gnomad AFR AF: 0.00310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000497 AC: 91 AN: 183197 Hom.: 0 AF XY: 0.000251 AC XY: 17 AN XY: 67647

Gnomad AFR exome AF: 0.00372

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000734

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000252 AC: 277 AN: 1098089 Hom.: 0 Cov.: 32 AF XY: 0.000237 AC XY: 86 AN XY: 363449

Gnomad4 AFR exome AF: 0.00337

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.00109 AC: 124 AN: 113349 Hom.: 0 Cov.: 24 AF XY: 0.000986 AC XY: 35 AN XY: 35499

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.000830

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.000945 Hom.: 9

Bravo AF: 0.00138

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2012	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2015	- -
Benign, no assertion criteria provided	curation	RettBASE	Mar 31, 2003	- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Oct 12, 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). -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

MECP2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2021

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). -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2017

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.56
Dann	Benign	0.71
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: rs61754439; hg19: chrX-153297825; COSMIC: COSV57655493; COSMIC: COSV57655493;