X-154031524-G-A

Position:

chrX-154031524-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001110792.2(MECP2):c.414-74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,132,367 control chromosomes in the GnomAD database, including 1,757 homozygotes. There are 6,272 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 133 hom., 694 hem., cov: 23)

Exomes 𝑓: 0.018 ( 1624 hom. 5578 hem. )

Consequence

MECP2
NM_001110792.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -0.111

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:

MECP2 (HGNC:):

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.414-74C>T		intron_variant		ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.378-74C>T		intron_variant		ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.414-74C>T		intron_variant		1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.378-74C>T		intron_variant		1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0182

AC:

2031

AN:

111782

Hom.:

133

Cov.:

AF XY:

0.0204

AC XY:

694

AN XY:

33954

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0763

Gnomad ASJ

AF:

0.000756

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.0119

Gnomad FIN

AF:

0.00344

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.0240

GnomAD4 exome

AF:

0.0180

AC:

18327

AN:

1020530

Hom.:

1624

AF XY:

0.0185

AC XY:

5578

AN XY:

302320

show subpopulations

Gnomad4 AFR exome

AF:

0.00148

Gnomad4 AMR exome

AF:

0.151

Gnomad4 ASJ exome

AF:

0.000424

Gnomad4 EAS exome

AF:

0.354

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.00550

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.0175

GnomAD4 genome

AF:

0.0181

AC:

2028

AN:

111837

Hom.:

133

Cov.:

AF XY:

0.0204

AC XY:

694

AN XY:

34019

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.0761

Gnomad4 ASJ

AF:

0.000756

Gnomad4 EAS

AF:

0.284

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.00344

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.00652

Hom.:

Bravo

AF:

0.0307

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, flagged submission	literature only	RettBASE	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 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). -

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Jun 12, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.076

DANN

Benign

0.49

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