rs782174572

Positions:

chrX-154030661-AGGTGGGGGCAGG-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2BP5BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Leu386_Pro389del variant in MECP2 (NM_004992.3) is 0.019% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Leu386_Pro389del variant is observed in 3 unaffected individuals (internal database) (BS2). The p.Leu386_Pro389del variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). The p.Leu386_Pro389del variant has been observed in 2 individuals with neurological disorders (PMID:19914908, 23262346) (PS4 not met). In summary, the p.Leu386_Pro389del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274655/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., 4 hem., cov: 0)

Exomes 𝑓: 0.000063 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 inframe_deletion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 3.20

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP5

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1191_1202del	p.Leu398_Pro401del	inframe_deletion	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.1155_1166del	p.Leu386_Pro389del	inframe_deletion	4/4	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.1155_1166del	p.Leu386_Pro389del	inframe_deletion	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000453960.7 linkuse as main transcript	c.1191_1202del	p.Leu398_Pro401del	inframe_deletion	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000407218.5 linkuse as main transcript	c.527_538del		3_prime_UTR_variant	4/4	5		ENSP00000384865
MECP2	ENST00000628176.2 linkuse as main transcript	c.527_538del		3_prime_UTR_variant	5/5	3		ENSP00000486978

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

16414

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

4652

FAILED QC

Gnomad AFR

AF:

0.000513

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000576

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000679

AC:

AN:

132529

Hom.:

AF XY:

0.0000408

AC XY:

AN XY:

49033

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000190

Gnomad ASJ exome

AF:

0.000180

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.000145

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000310

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000635

AC:

AN:

535603

Hom.:

AF XY:

0.0000255

AC XY:

AN XY:

156629

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000172

Gnomad4 ASJ exome

AF:

0.000130

Gnomad4 EAS exome

AF:

0.000255

Gnomad4 SAS exome

AF:

0.0000898

Gnomad4 FIN exome

AF:

0.0000758

Gnomad4 NFE exome

AF:

0.0000554

Gnomad4 OTH exome

AF:

0.0000528

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000426

AC:

AN:

16414

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

4652

show subpopulations

Gnomad4 AFR

AF:

0.000513

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000576

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Uncertain:1Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 09, 2022	The allele frequency of the p.Leu386_Pro389del variant in MECP2 (NM_004992.3) is 0.019% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Leu386_Pro389del variant is observed in 3 unaffected individuals (internal database) (BS2). The p.Leu386_Pro389del variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). The p.Leu386_Pro389del variant has been observed in 2 individuals with neurological disorders (PMID: 19914908, 23262346) (PS4 not met). In summary, the p.Leu386_Pro389del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5). -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 15, 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). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Jun 12, 2013	- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2020

This variant is associated with the following publications: (PMID: 23262346, 19914908) -

MECP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2023

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

Splicing

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