rs2075597

Positions:

chrX-154032185-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001110792.2(MECP2):c.413+22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00688 in 1,162,678 control chromosomes in the GnomAD database, including 231 homozygotes. There are 2,465 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 23 hom., 357 hem., cov: 24)

Exomes 𝑓: 0.0066 ( 208 hom. 2108 hem. )

Consequence

MECP2
NM_001110792.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.426

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 -20 ACMG points.

BP4

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

BP6

Variant X-154032185-G-C is Benign according to our data. Variant chrX-154032185-G-C is described in ClinVar as [Benign]. Clinvar id is 156054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154032185-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0948 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.413+22C>G		intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.377+22C>G		intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11 linkuse as main transcript	c.377+22C>G		intron_variant		1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000453960.7 linkuse as main transcript	c.413+22C>G		intron_variant		1	NM_001110792.2	ENSP00000395535		P51608-2

Frequencies

GnomAD3 genomes

AF:

0.00911

AC:

1029

AN:

113000

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

358

AN XY:

35136

show subpopulations

Gnomad AFR

AF:

0.00315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0442

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.00648

Gnomad FIN

AF:

0.00191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000769

Gnomad OTH

AF:

0.00920

GnomAD3 exomes

AF:

0.0215

AC:

3920

AN:

182491

Hom.:

121

AF XY:

0.0166

AC XY:

1113

AN XY:

67181

show subpopulations

Gnomad AFR exome

AF:

0.00237

Gnomad AMR exome

AF:

0.0809

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.104

Gnomad SAS exome

AF:

0.00377

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.000727

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.00664

AC:

6971

AN:

1049624

Hom.:

208

Cov.:

AF XY:

0.00651

AC XY:

2108

AN XY:

323956

show subpopulations

Gnomad4 AFR exome

AF:

0.00133

Gnomad4 AMR exome

AF:

0.0743

Gnomad4 ASJ exome

AF:

0.000314

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.00468

Gnomad4 FIN exome

AF:

0.00138

Gnomad4 NFE exome

AF:

0.000495

Gnomad4 OTH exome

AF:

0.00742

GnomAD4 genome

AF:

0.00907

AC:

1025

AN:

113054

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

357

AN XY:

35200

show subpopulations

Gnomad4 AFR

AF:

0.00314

Gnomad4 AMR

AF:

0.0439

Gnomad4 ASJ

AF:

0.000377

Gnomad4 EAS

AF:

0.103

Gnomad4 SAS

AF:

0.00614

Gnomad4 FIN

AF:

0.00191

Gnomad4 NFE

AF:

0.000769

Gnomad4 OTH

AF:

0.00909

Alfa

AF:

0.00532

Hom.:

Bravo

AF:

0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 30, 2020	- -
not provided, flagged submission	literature only	RettBASE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2) -

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Dec 05, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.080

DANN

Benign

0.63

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