rs5987194

Variant names:

• chrX-154036016-C-G
• rs5987194
• NM_001110792.2:c.63-3459G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001110792.2(MECP2):​c.63-3459G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.81 (26828 hom., 25062 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.77
• Publications: 18 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).

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.63-3459G>C		intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.27-3459G>C		intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.-253-3459G>C		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.63-3459G>C		intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.27-3459G>C		intron	N/A	ENSP00000301948.6
	MECP2	ENST00000496908.5	TSL:1	n.158-3459G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.809 AC: 88580 AN: 109494 Hom.: 26827 Cov.: 22

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.755

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: 0.809 AC: 88615 AN: 109538 Hom.: 26828 Cov.: 22 AF XY: 0.788 AC XY: 25062 AN XY: 31816

African (AFR) AF: 0.877 AC: 26401 AN: 30098

American (AMR) AF: 0.623 AC: 6410 AN: 10283

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 2039 AN: 2614

East Asian (EAS) AF: 0.237 AC: 830 AN: 3498

South Asian (SAS) AF: 0.397 AC: 989 AN: 2493

European-Finnish (FIN) AF: 0.857 AC: 4861 AN: 5670

Middle Eastern (MID) AF: 0.687 AC: 149 AN: 217

European-Non Finnish (NFE) AF: 0.860 AC: 45158 AN: 52494

Other (OTH) AF: 0.754 AC: 1125 AN: 1492

Alfa AF: 0.832 Hom.: 7147

Bravo AF: 0.794

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.85
DANN	Benign	0.37
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs5987194; hg19: chrX-153301467;