rs267608406

chrX-154030648-CGGGCTCAGGTGGAGGTGG-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.1198_1215del(p.Pro400_Pro405del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000747 in 803,418 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P400P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., 3 hem., cov: 0)
  • Exomes 𝑓: 0.000075 (0 hom. 20 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 inframe_deletion
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 5.37

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 11 uncertain in NM_001110792.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2.
• BP6: Variant X-154030648-CGGGCTCAGGTGGAGGTGG-C is Benign according to our data. Variant chrX-154030648-CGGGCTCAGGTGGAGGTGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 143396.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030648-CGGGCTCAGGTGGAGGTGG-C is described in Lovd as [Pathogenic]. Variant chrX-154030648-CGGGCTCAGGTGGAGGTGG-C is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1198_1215del	p.Pro400_Pro405del	inframe_deletion	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1162_1179del	p.Pro388_Pro393del	inframe_deletion	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1162_1179del	p.Pro388_Pro393del	inframe_deletion	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1198_1215del	p.Pro400_Pro405del	inframe_deletion	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*534_*551del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*534_*551del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7 AN: 72333 Hom.: 0 Cov.: 0 AF XY: 0.000187 AC XY: 3 AN XY: 16021 FAILED QC

Gnomad AFR AF: 0.0000558

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: 0.000151

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000408 AC: 7 AN: 171619 Hom.: 0 AF XY: 0.0000480 AC XY: 3 AN XY: 62443

Gnomad AFR exome AF: 0.000172

Gnomad AMR exome AF: 0.0000374

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: 0.0000519

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000747 AC: 60 AN: 803418 Hom.: 0 AF XY: 0.0000820 AC XY: 20 AN XY: 243984

Gnomad4 AFR exome AF: 0.000207

Gnomad4 AMR exome AF: 0.0000341

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000693

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000819

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000968 AC: 7 AN: 72333 Hom.: 0 Cov.: 0 AF XY: 0.000187 AC XY: 3 AN XY: 16021

Gnomad4 AFR AF: 0.0000558

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: 0.000151

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 1

Bravo AF: 0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	curation	RettBASE	Nov 01, 2011	- -

Rett syndrome Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 22, 2021	The allele frequency of the p.Pro388_Pro393del (NM_004992.3) variant in MECP2 is 0.01% in the African/African 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.Pro388_Pro393del variant is observed in at least 1 unaffected individual (PMID 21160487)(BS2_supporting). The p.Pro388_Pro393del variant is found in a patient with an alternate molecular basis of disease (PMID 21160487)(BP5). In summary, the p.Pro388_Pro393del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BS2_supporting, BP5). -
Likely 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 likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting). Variant is found in an individual with an alternate molecular basis of disease (BP5). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2018

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 02, 2023

- -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2022

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: rs267608406; hg19: chrX-153296099;