rs61753008

Positions:

• chrX-154030654-CAGGTGG-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1 PM4 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.1204_1209del​(p.Pro402_Pro403del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000144 in 1,169,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P402P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.00014 (0 hom. 48 hem.)
• Consequence: MECP2 NM_001110792.2 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.01

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 -8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 12 uncertain in NM_001110792.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2.
• BP6: Variant X-154030654-CAGGTGG-C is Benign according to our data. Variant chrX-154030654-CAGGTGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 143412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030654-CAGGTGG-C is described in Lovd as [Likely_benign]. Variant chrX-154030654-CAGGTGG-C is described in Lovd as [Pathogenic]. Variant chrX-154030654-CAGGTGG-C is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAdExome4 at 48 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1204_1209del	p.Pro402_Pro403del	inframe_deletion	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1168_1173del	p.Pro390_Pro391del	inframe_deletion	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1168_1173del	p.Pro390_Pro391del	inframe_deletion	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1204_1209del	p.Pro402_Pro403del	inframe_deletion	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*540_*545del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*540_*545del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 12 AN: 90582 Hom.: 0 Cov.: 0 AF XY: 0.0000469 AC XY: 1 AN XY: 21312

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000506

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000108

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000635 AC: 11 AN: 173240 Hom.: 0 AF XY: 0.0000788 AC XY: 5 AN XY: 63422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 156 AN: 1079130 Hom.: 0 AF XY: 0.000137 AC XY: 48 AN XY: 350942

Gnomad4 AFR exome AF: 0.0000765

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000566

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000132 AC: 12 AN: 90585 Hom.: 0 Cov.: 0 AF XY: 0.0000469 AC XY: 1 AN XY: 21323

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000129

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000510

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000108

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 2

Bravo AF: 0.000106

Asia WGS AF: 0.000398 AC: 1 AN: 2521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	curation	RettBASE	Feb 05, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Rett syndrome Benign:2

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 Specifications 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). -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 07, 2015	- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2014

The c.1168_1173delCCACCT variant in the MECP2 gene has been reported previously in girl with Rett syndrome (Djarmati et al., 2007). The deletion causes an in-frame loss of two Proline amino acids at codon 390 and 391, denoted p.Pro390_Pro391del. The c.1168_1173delCCACCT variant is described as a polymorphism in a gene specific mutation database as this variant was reported in an unaffected family member. Additionally, this variant is present in the NHLBI Exome Sequencing Project using alternate transcript numbering and has been observed in the homozygous state in a female and hemizygous in three males. This variant has been observed to be maternally inherited. The variant is found in MECP2 panel(s). -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61753008; hg19: chrX-153296105;