rs1734792

Variant names:

• chrX-154075609-C-A
• rs1734792
• NM_001110792.2:c.62+21995G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154075609-C-A
• chrX-154075609-C-T

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.62+21995G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 110,120 control chromosomes in the GnomAD database, including 2,527 homozygotes. There are 7,213 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.22 (2527 hom., 7213 hem., cov: 22)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.256
• Publications: 14 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, 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

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant X-154075609-C-A is Benign according to our data. Variant chrX-154075609-C-A is described in ClinVar as Benign. ClinVar VariationId is 3602013.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.62+21995G>T		intron	N/A	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.26+16575G>T		intron	N/A	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-422+16575G>T		intron	N/A	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.62+21995G>T		intron	N/A	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.26+16575G>T		intron	N/A	ENSP00000301948.6	P51608-1
	MECP2	ENST00000496908.5	TSL:1	n.157+21204G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.217 AC: 23850 AN: 110070 Hom.: 2527 Cov.: 22

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.0397

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.217 AC: 23858 AN: 110120 Hom.: 2527 Cov.: 22 AF XY: 0.222 AC XY: 7213 AN XY: 32424

African (AFR) AF: 0.220 AC: 6666 AN: 30258

American (AMR) AF: 0.384 AC: 3922 AN: 10206

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 574 AN: 2633

East Asian (EAS) AF: 0.751 AC: 2614 AN: 3479

South Asian (SAS) AF: 0.563 AC: 1442 AN: 2561

European-Finnish (FIN) AF: 0.135 AC: 785 AN: 5823

Middle Eastern (MID) AF: 0.321 AC: 69 AN: 215

European-Non Finnish (NFE) AF: 0.140 AC: 7367 AN: 52772

Other (OTH) AF: 0.263 AC: 392 AN: 1493

Alfa AF: 0.200 Hom.: 3708

Bravo AF: 0.242

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
PhyloP100		-0.26

Splicing

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

Other links and lift over

dbSNP: rs1734792; hg19: chrX-153341060;