X-154046529-T-A

Variant names:

• chrX-154046529-T-A
• rs17435
• NM_001110792.2:c.63-13972A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001110792.2(MECP2):​c.63-13972A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.64 (17489 hom., 19996 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09
• Publications: 36 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-154046529-T-A is Benign according to our data. Variant chrX-154046529-T-A is described in ClinVar as Benign. ClinVar VariationId is 3602068.Status of the report is criteria_provided_single_submitter, 1 stars.

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.63-13972A>T		intron	N/A	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.27-13972A>T		intron	N/A	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-254+11870A>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.63-13972A>T		intron	N/A	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.27-13972A>T		intron	N/A	ENSP00000301948.6	P51608-1
	MECP2	ENST00000496908.5	TSL:1	n.158-13972A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.636 AC: 69632 AN: 109564 Hom.: 17498 Cov.: 22

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.965

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.600

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: 0.635 AC: 69629 AN: 109618 Hom.: 17489 Cov.: 22 AF XY: 0.626 AC XY: 19996 AN XY: 31920

African (AFR) AF: 0.393 AC: 11827 AN: 30074

American (AMR) AF: 0.535 AC: 5493 AN: 10276

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 1931 AN: 2619

East Asian (EAS) AF: 0.225 AC: 781 AN: 3465

South Asian (SAS) AF: 0.402 AC: 1028 AN: 2559

European-Finnish (FIN) AF: 0.802 AC: 4589 AN: 5721

Middle Eastern (MID) AF: 0.620 AC: 134 AN: 216

European-Non Finnish (NFE) AF: 0.806 AC: 42306 AN: 52516

Other (OTH) AF: 0.592 AC: 883 AN: 1491

Alfa AF: 0.547 Hom.: 2350

Bravo AF: 0.602

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	-0.85
CADD	Benign	0.33
DANN	Benign	0.81
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs17435; hg19: chrX-153311980;