rs267608446

Variant names:

• chrX-154032308-TC-T
• rs267608446
• NM_001110792.2:c.311delG

Your query was ambiguous. Multiple possible variants found:

• chrX-154032308-TC-T
• chrX-154032308-TC-TCC
• chrX-154032308-TC-TCCC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.311delG​(p.Gly104AspfsTer33) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G104G) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.08
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154032308-TC-T is Pathogenic according to our data. Variant chrX-154032308-TC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 156609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.311delG	p.Gly104AspfsTer33	frameshift_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.275delG	p.Gly92AspfsTer33	frameshift_variant	Exon 3 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.311delG	p.Gly104AspfsTer33	frameshift_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.275delG	p.Gly92AspfsTer33	frameshift_variant	Exon 3 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed frameshift c.311del(p.Gly104AspfsTer33) variant in MECP2 gene has been submitted to the ClinVar database as Pathogenic. The p.Gly104AspfsTer33 variant is absent in gnomAD Exomes. This variant causes a frameshift starting with codon Glycine 104, changes this amino acid to Aspartic Acid residue, and creates a premature Stop codon at position 33 of the new reading frame, denoted p.Gly104AspfsTer33. This variant is predicted to cause loss of normal protein function through protein truncation. Multiple loss of function variants have been reported downstream of this position. However, additional functional studies will be required to prove the pathogenicity of this variant as it is present in the penultimate exon. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Aug 12, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275delG mutation in the MECP2 gene causes a frameshift starting with codon Glycine 92, changes this amino acid to an Aspartic acid residue and creates a premature Stop codon at position 33 of the new reading frame, denoted p.Gly92AspfsX33. This mutation is predicted to cause loss of normal protein function through protein truncation, as the last 395 amino acids of the MECP2 protein are replaced with 32 aberrant amino acids. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267608446; hg19: chrX-153297759; COSMIC: COSV57652163; COSMIC: COSV57652163;