rs267608604

chrX-154030655-AGGTGGAGGT-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM4 BP6

The NM_001110792.2(MECP2):c.1200_1208del(p.Pro401_Pro403del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000147 in 748,978 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P400P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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 Uncertain_significance. Variant got 3 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-154030655-AGGTGGAGGT-A is Benign according to our data. Variant chrX-154030655-AGGTGGAGGT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143404.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1200_1208del	p.Pro401_Pro403del	inframe_deletion	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1164_1172del	p.Pro389_Pro391del	inframe_deletion	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1164_1172del	p.Pro389_Pro391del	inframe_deletion	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.1200_1208del	p.Pro401_Pro403del	inframe_deletion	3/3	1	NM_001110792.2
MECP2	ENST00000407218.5	c.*536_*544del		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*536_*544del		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000120 AC: 2 AN: 166750 Hom.: 0 AF XY: 0.0000166 AC XY: 1 AN XY: 60332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000776

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 11 AN: 748978 Hom.: 0 AF XY: 0.00000890 AC XY: 2 AN XY: 224762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000787

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000168

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rett syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 20, 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 likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD V4 is between 0.008% and 0.03% (BS1). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Apr 10, 2002	- -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2021

This variant, c.1164_1172del, results in the deletion of 3 amino acid(s) of the MECP2 protein (p.Pro389_Pro391del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs267608604, ExAC 0.02%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with Rett syndrome. In addition, a different variant (c.1158_1166del) giving rise to the same protein effect observed here (p.Pro389_Pro391del) has been observed in an individual affected with Rett syndrome (PMID: 11055898, 19914908). ClinVar contains an entry for this variant (Variation ID: 143404). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs267608604; hg19: chrX-153296106;