NM_001110792.2:c.413+24C>A

Variant names:

• chrX-154032183-G-T
• rs267608462
• NM_001110792.2:c.413+24C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.377+24C>A variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed 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). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+24C>A variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199494/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000012 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3 O:1
• Conservation: PhyloP100: 1.42
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.413+24C>A		intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.377+24C>A		intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.98+24C>A		intron	N/A	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.413+24C>A		intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.377+24C>A		intron	N/A	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.377+24C>A		intron	N/A	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 112978 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000932

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 8 AN: 182455 AF XY: 0.0000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 13 AN: 1046142 Hom.: 0 Cov.: 25 AF XY: 0.00000933 AC XY: 3 AN XY: 321534

African (AFR) AF: 0.00 AC: 0 AN: 25383

American (AMR) AF: 0.000114 AC: 4 AN: 35148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19056

East Asian (EAS) AF: 0.00 AC: 0 AN: 30003

South Asian (SAS) AF: 0.00 AC: 0 AN: 52913

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40437

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3976

European-Non Finnish (NFE) AF: 0.0000101 AC: 8 AN: 794849

Other (OTH) AF: 0.0000225 AC: 1 AN: 44377

GnomAD4 genome AF: 0.00000885 AC: 1 AN: 112978 Hom.: 0 Cov.: 24 AF XY: 0.0000285 AC XY: 1 AN XY: 35116

African (AFR) AF: 0.00 AC: 0 AN: 31151

American (AMR) AF: 0.0000932 AC: 1 AN: 10733

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3609

South Asian (SAS) AF: 0.00 AC: 0 AN: 2778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6263

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53339

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

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

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Benign:2

Oct 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the c.377+24C>A variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed 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). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+24C>A variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS1, BP4).

Oct 12, 2023

Centre for Population Genomics, CPG

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 ExAC is between 0.008% and 0.03% (BS1). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7).

X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1

Mar 10, 2010

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Jul 30, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Other:1

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.77
PhyloP100		1.4
PromoterAI		-0.062	Neutral
Mutation Taster		=100/0	polymorphism

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: rs267608462; hg19: chrX-153297634;