rs7884181

Variant names:

• chrX-154133040-C-T
• rs7884181
• ENST00000631210.1:n.47+4017G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000631210.1(MECP2):​n.47+4017G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 110,718 control chromosomes in the GnomAD database, including 2,073 homozygotes. There are 5,615 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2073 hom., 5615 hem., cov: 22)
• Consequence: MECP2 ENST00000631210.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.214
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000631210.1	n.47+4017G>A		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 20623 AN: 110665 Hom.: 2062 Cov.: 22

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.0878

Gnomad AMR AF: 0.0928

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00962

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0770

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.187 AC: 20687 AN: 110718 Hom.: 2073 Cov.: 22 AF XY: 0.170 AC XY: 5615 AN XY: 32982

African (AFR) AF: 0.388 AC: 11746 AN: 30262

American (AMR) AF: 0.0926 AC: 968 AN: 10454

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 307 AN: 2640

East Asian (EAS) AF: 0.00936 AC: 33 AN: 3525

South Asian (SAS) AF: 0.0445 AC: 118 AN: 2654

European-Finnish (FIN) AF: 0.0770 AC: 458 AN: 5951

Middle Eastern (MID) AF: 0.147 AC: 32 AN: 218

European-Non Finnish (NFE) AF: 0.127 AC: 6725 AN: 52836

Other (OTH) AF: 0.161 AC: 240 AN: 1495

Alfa AF: 0.174 Hom.: 9014

Bravo AF: 0.200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.24
DANN	Benign	0.72
PhyloP100		-0.21

Splicing

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

Other links and lift over

dbSNP: rs7884181; hg19: chrX-153398515;