rs61752980

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001110792.2(MECP2):c.1173C>T(p.Pro391=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,201,914 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 105 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. P391P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 8 hem., cov: 22)

Exomes 𝑓: 0.00022 ( 0 hom. 97 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.245

Variant links:

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]

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant X-154030691-G-A is Benign according to our data. Variant chrX-154030691-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030691-G-A is described in Lovd as [Pathogenic]. Variant chrX-154030691-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.245 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000222 (242/1092169) while in subpopulation MID AF= 0.00135 (5/3704). AF 95% confidence interval is 0.000532. There are 0 homozygotes in gnomad4_exome. There are 97 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1173C>T	p.Pro391=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.1137C>T	p.Pro379=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1173C>T	p.Pro391=	synonymous_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1137C>T	p.Pro379=	synonymous_variant	4/4	1	NM_004992.4	P1	P51608-1
MECP2	ENST00000407218.5 linkuse as main transcript	c.*509C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2 linkuse as main transcript	c.*509C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

109745

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

AN XY:

31953

show subpopulations

Gnomad AFR

AF:

0.0000664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000578

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000286

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000153

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000345

AC:

AN:

173766

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

62246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.00126

Gnomad EAS exome

AF:

0.0000733

Gnomad SAS exome

AF:

0.000377

Gnomad FIN exome

AF:

0.0000713

Gnomad NFE exome

AF:

0.000363

Gnomad OTH exome

AF:

0.000693

GnomAD4 exome

AF:

0.000222

AC:

242

AN:

1092169

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

359061

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000371

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000408

Gnomad4 FIN exome

AF:

0.0000260

Gnomad4 NFE exome

AF:

0.000179

Gnomad4 OTH exome

AF:

0.000371

GnomAD4 genome

AF:

0.000191

AC:

AN:

109745

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

AN XY:

31953

show subpopulations

Gnomad4 AFR

AF:

0.0000664

Gnomad4 AMR

AF:

0.000578

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000286

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000168

Gnomad4 NFE

AF:

0.000153

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000351

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 26, 2016	Variant summary: The MECP2 c.1137C>T (p.Pro379Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 29/80063 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0005728 (25/43643). This frequency is about 69 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MECP2: BP4, BP7, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2013	- -
Benign, no assertion criteria provided	curation	RettBASE	Dec 20, 2002	- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Rett syndrome

Benign:1

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). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

History of neurodevelopmental disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2017

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

MECP2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 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

-0.98

Cadd

Benign

0.042

Dann

Benign

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over