rs782174572

Variant names:

• chrX-154030661-AGGTGGGGGCAGG-A
• rs782174572
• NM_001110792.2:c.1191_1202delCCTGCCCCCACC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP5 BS1 BS2

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 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 3.20

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]

ACMG classification

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 rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1191_1202delCCTGCCCCCACC	p.Leu398_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1155_1166delCCTGCCCCCACC	p.Leu386_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1191_1202delCCTGCCCCCACC	p.Leu398_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1155_1166delCCTGCCCCCACC	p.Leu386_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7 AN: 16414 Hom.: 0 Cov.: 0 AF XY: 0.000860 AC XY: 4 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: 9 AN: 132529 Hom.: 0 AF XY: 0.0000408 AC XY: 2 AN XY: 49033

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: 34 AN: 535603 Hom.: 0 AF XY: 0.0000255 AC XY: 4 AN XY: 156629

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: 7 AN: 16414 Hom.: 0 Cov.: 0 AF XY: 0.000860 AC XY: 4 AN XY: 4652

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:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:1 Benign:2

Dec 09, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Jun 12, 2013

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jan 15, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

MECP2-related disorder Benign:1

Aug 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782174572; hg19: chrX-153296112;