X-154065469-A-T

Variant names:

• chrX-154065469-A-T
• rs1734791
• NM_001110792.2:c.62+32135T>A

Variant summary

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

The NM_001110792.2(MECP2):​c.62+32135T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 111,070 control chromosomes in the GnomAD database, including 2,794 homozygotes. There are 7,835 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 0.23 (2794 hom., 7835 hem., cov: 21)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.62+32135T>A		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.26+26715T>A		intron_variant	Intron 2 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.62+32135T>A		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.26+26715T>A		intron_variant	Intron 2 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.229 AC: 25397 AN: 111017 Hom.: 2794 Cov.: 21

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.765

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.317

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.229 AC: 25410 AN: 111070 Hom.: 2794 Cov.: 21 AF XY: 0.235 AC XY: 7835 AN XY: 33320

African (AFR) AF: 0.258 AC: 7871 AN: 30548

American (AMR) AF: 0.387 AC: 4061 AN: 10500

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 580 AN: 2641

East Asian (EAS) AF: 0.765 AC: 2647 AN: 3459

South Asian (SAS) AF: 0.579 AC: 1517 AN: 2621

European-Finnish (FIN) AF: 0.134 AC: 803 AN: 5988

Middle Eastern (MID) AF: 0.324 AC: 71 AN: 219

European-Non Finnish (NFE) AF: 0.140 AC: 7425 AN: 52903

Other (OTH) AF: 0.272 AC: 411 AN: 1509

Alfa AF: 0.148 Hom.: 3151

Bravo AF: 0.254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.85
PhyloP100		1.7
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: rs1734791; hg19: chrX-153330920;