rs1734787

Variant names:

• chrX-154059995-A-C
• rs1734787
• NM_001110792.2:c.63-27438T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154059995-A-C
• chrX-154059995-A-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001110792.2(MECP2):​c.63-27438T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 751,542 control chromosomes in the GnomAD database, including 7,905 homozygotes. There are 32,788 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2116 hom., 6281 hem., cov: 22)
  • Exomes 𝑓: 0.14 (5789 hom. 26507 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.645
• Publications: 26 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-154059995-A-C is Benign according to our data. Variant chrX-154059995-A-C is described in ClinVar as Benign. ClinVar VariationId is 3602069.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

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.63-27438T>G		intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.27-27438T>G		intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.-421-1429T>G		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.63-27438T>G		intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.27-27438T>G		intron	N/A	ENSP00000301948.6
	MECP2	ENST00000496908.5	TSL:1	n.158-27438T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.180 AC: 19931 AN: 110819 Hom.: 2117 Cov.: 22

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.0364

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.292

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.137 AC: 87588 AN: 640668 Hom.: 5789 Cov.: 28 AF XY: 0.138 AC XY: 26507 AN XY: 192298

African (AFR) AF: 0.0808 AC: 1002 AN: 12407

American (AMR) AF: 0.438 AC: 358 AN: 817

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 968 AN: 3972

East Asian (EAS) AF: 0.779 AC: 2355 AN: 3022

South Asian (SAS) AF: 0.561 AC: 6727 AN: 11993

European-Finnish (FIN) AF: 0.179 AC: 47 AN: 263

Middle Eastern (MID) AF: 0.389 AC: 430 AN: 1105

European-Non Finnish (NFE) AF: 0.121 AC: 71020 AN: 585920

Other (OTH) AF: 0.221 AC: 4681 AN: 21169

GnomAD4 genome AF: 0.180 AC: 19932 AN: 110874 Hom.: 2116 Cov.: 22 AF XY: 0.190 AC XY: 6281 AN XY: 33098

African (AFR) AF: 0.0883 AC: 2709 AN: 30690

American (AMR) AF: 0.365 AC: 3792 AN: 10376

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 569 AN: 2625

East Asian (EAS) AF: 0.769 AC: 2670 AN: 3474

South Asian (SAS) AF: 0.590 AC: 1457 AN: 2471

European-Finnish (FIN) AF: 0.151 AC: 897 AN: 5944

Middle Eastern (MID) AF: 0.302 AC: 65 AN: 215

European-Non Finnish (NFE) AF: 0.140 AC: 7382 AN: 52876

Other (OTH) AF: 0.241 AC: 366 AN: 1517

Alfa AF: 0.170 Hom.: 9041

Bravo AF: 0.197

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Benign:1

Dec 02, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). The computational splicing predictor SpliceAI do not support significant splicing alteration (score of <=0.1) 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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.65
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: rs1734787; hg19: chrX-153325446;