X-154031941-A-G

Position:

• chrX-154031941-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000453960.7(MECP2):​c.413+266T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (28382 hom., 27451 hem., cov: 24)
  • Failed GnomAD Quality Control
• Consequence: MECP2 ENST00000453960.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.0690

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant X-154031941-A-G is Benign according to our data. Variant chrX-154031941-A-G is described in ClinVar as [Benign]. Clinvar id is 156056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031941-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.413+266T>C		intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.377+266T>C		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+266T>C		intron_variant		1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.377+266T>C		intron_variant		1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.831 AC: 92717 AN: 111618 Hom.: 28382 Cov.: 24 AF XY: 0.811 AC XY: 27395 AN XY: 33778

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.775

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.831 AC: 92769 AN: 111672 Hom.: 28382 Cov.: 24 AF XY: 0.811 AC XY: 27451 AN XY: 33842

Gnomad4 AFR AF: 0.948

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.783

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.863

Gnomad4 OTH AF: 0.774

Alfa AF: 0.811 Hom.: 8211

Bravo AF: 0.817

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, flagged submission	literature only	RettBASE	-	- -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Aug 24, 2010

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 15, 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 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.6
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075596; hg19: chrX-153297392;