X-154030967-G-A

Position:

chrX-154030967-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000453960.7(MECP2):c.897C>T(p.Ala299=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,210,374 control chromosomes in the GnomAD database, including 1 homozygotes. There are 65 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. A299A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00018 ( 1 hom. 61 hem. )

Consequence

MECP2
ENST00000453960.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.82

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-154030967-G-A is Benign according to our data. Variant chrX-154030967-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.82 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.897C>T	p.Ala299=	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.861C>T	p.Ala287=	synonymous_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.897C>T	p.Ala299=	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.861C>T	p.Ala287=	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

112172

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34338

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000934

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.000664

GnomAD3 exomes

AF:

0.000207

AC:

AN:

183217

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

67729

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000577

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000179

AC:

197

AN:

1098202

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

363568

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000170

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.000430

Gnomad4 SAS exome

AF:

0.000295

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.000195

GnomAD4 genome

AF:

0.000134

AC:

AN:

112172

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34338

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.0000934

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.000664

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000140

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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	Jul 01, 2023	MECP2: BP4, BP7, BS2 -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 12, 2015

- -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.0

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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