chrX-154117689-T-G

Variant names:

• chrX-154117689-T-G
• rs5945176
• ENST00000631210.1:n.48-12651A>C

Variant summary

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

The ENST00000631210.1(MECP2):​n.48-12651A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 110,700 control chromosomes in the GnomAD database, including 5,583 homozygotes. There are 11,481 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 0.35 (5583 hom., 11481 hem., cov: 23)
• Consequence: MECP2 ENST00000631210.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 2 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 = 0.525 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000631210.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000631210.1	TSL:1	n.48-12651A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.353 AC: 39015 AN: 110644 Hom.: 5582 Cov.: 23

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.0540

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.356

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.353 AC: 39035 AN: 110700 Hom.: 5583 Cov.: 23 AF XY: 0.349 AC XY: 11481 AN XY: 32940

African (AFR) AF: 0.532 AC: 16173 AN: 30382

American (AMR) AF: 0.242 AC: 2506 AN: 10344

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 885 AN: 2625

East Asian (EAS) AF: 0.361 AC: 1277 AN: 3541

South Asian (SAS) AF: 0.515 AC: 1365 AN: 2651

European-Finnish (FIN) AF: 0.311 AC: 1809 AN: 5826

Middle Eastern (MID) AF: 0.376 AC: 80 AN: 213

European-Non Finnish (NFE) AF: 0.272 AC: 14398 AN: 52933

Other (OTH) AF: 0.337 AC: 505 AN: 1500

Alfa AF: 0.310 Hom.: 3067

Bravo AF: 0.355

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.3
DANN	Benign	0.65
PhyloP100		-0.23

Splicing

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

Other links and lift over

dbSNP: rs5945176; hg19: chrX-153383163;