rs267608459

Positions:

• chrX-154032197-TCTTA-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6_Very_Strong BS2_Supporting

The NM_001110792.2(MECP2):​c.413+6_413+9delTAAG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000647 in 1,081,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000065 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 splice_region, intron
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3 O:1
• Conservation: PhyloP100: 6.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-154032197-TCTTA-T is Benign according to our data. Variant chrX-154032197-TCTTA-T is described in ClinVar as [Likely_benign]. Clinvar id is 156059.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.413+6_413+9delTAAG		splice_region_variant, intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.377+6_377+9delTAAG		splice_region_variant, intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.413+6_413+9delTAAG		splice_region_variant, intron_variant		1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.377+6_377+9delTAAG		splice_region_variant, intron_variant		1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183016 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000647 AC: 7 AN: 1081701 Hom.: 0 AF XY: 0.00000574 AC XY: 2 AN XY: 348439

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.0000220

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2024	Variant summary: MECP2 c.377+6_377+9delTAAG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. Two predict the variant creates a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.9e-06 in 1195715 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.377+6_377+9delTAAG has been reported in the literature in at-least one individual affected with infantile autism (example: Lam_2000). These report(s) do not provide unequivocal conclusions about association of the variant with Rett Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 11106359). ClinVar contains an entry for this variant (Variation ID: 156059). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2018	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. -

not provided Uncertain:1 Other:1

not provided, flagged submission	literature only	RettBASE	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 14, 2021	The MECP2 c.377+6_377+9delTAAG variant (rs267608459), also known as IVS2+2delTAAG, has not been reported in individuals with Rett syndrome but has been observed in an individual with infantile autism (Lam 2000). This variant is also reported in ClinVar (Variation ID: 156059). This variant is found in the East Asian population with an allele frequency of 0.01% (2/13,856 alleles) in the Genome Aggregation Database. This is an intronic variant, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weaking the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.377+6_377+9delTAAG variant is uncertain at this time. References: Lam CW et al. Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet. 2000 Dec;37(12):E41. PMID: 11106359. -

Rett syndrome Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 26, 2021	The allele frequency of the c.377+6_377+9del variant in MECP2 (NM_004992.3) is 0.014% in the East Asian 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 c.377+6_377+9del variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the c.377+6_377+9del variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP5). -
Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 18, 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 is between 0.008% and 0.03% (BS1). -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This sequence change falls in intron 3 of the MECP2 gene. It does not directly change the encoded amino acid sequence of the MECP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs267608459, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with autism (PMID: 11106359). This variant is also known as IVS+2delTAAG. ClinVar contains an entry for this variant (Variation ID: 156059). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Autism, susceptibility to, X-linked 3 Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Sep 05, 2002

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 31

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608459; hg19: chrX-153297648;