rs61749711

chrX-154031246-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.618C>T(p.Ser206=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,209,931 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,176 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 0.0020 (1 hom., 59 hem., cov: 23)
  • Exomes 𝑓: 0.0032 (4 hom. 1117 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0860

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 (MetaRNN=0.008058667).
• BP6: Variant X-154031246-G-A is Benign according to our data. Variant chrX-154031246-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031246-G-A is described in Lovd as [Likely_benign]. Variant chrX-154031246-G-A is described in Lovd as [Benign]. Variant chrX-154031246-G-A is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-0.086 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00195 (218/111719) while in subpopulation NFE AF= 0.00309 (164/53010). AF 95% confidence interval is 0.00271. There are 1 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 59 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.618C>T	p.Ser206=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.582C>T	p.Ser194=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.618C>T	p.Ser206=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.582C>T	p.Ser194=	synonymous_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 218 AN: 111669 Hom.: 1 Cov.: 23 AF XY: 0.00174 AC XY: 59 AN XY: 33861

Gnomad AFR AF: 0.000686

Gnomad AMI AF: 0.00733

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00152

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.00262

Gnomad FIN AF: 0.000494

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00230 AC: 421 AN: 183308 Hom.: 1 AF XY: 0.00233 AC XY: 158 AN XY: 67812

Gnomad AFR exome AF: 0.000761

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.000312

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00317 AC: 3484 AN: 1098212 Hom.: 4 Cov.: 35 AF XY: 0.00307 AC XY: 1117 AN XY: 363574

Gnomad4 AFR exome AF: 0.000682

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.000619

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.000518

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00271

GnomAD4 genome AF: 0.00195 AC: 218 AN: 111719 Hom.: 1 Cov.: 23 AF XY: 0.00174 AC XY: 59 AN XY: 33923

Gnomad4 AFR AF: 0.000684

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00152

Gnomad4 EAS AF: 0.000565

Gnomad4 SAS AF: 0.00263

Gnomad4 FIN AF: 0.000494

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00229 Hom.: 18

Bravo AF: 0.00187

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00342 AC: 23

ExAC AF: 0.00222 AC: 270

EpiCase AF: 0.00305

EpiControl AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 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, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 22, 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). -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2016

This alteration is classified as benign based on a combination of the following: 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. -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 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_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.88
Dann	Benign	0.52
DEOGEN2	Benign	0.075	T;T
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0081	T;T
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	1.0	D;D;N
Sift4G	Uncertain	0.052	T;T
Vest4		0.24
MVP		0.98
ClinPred		0.0073	T
GERP RS		-4.8
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: rs61749711; hg19: chrX-153296697;