X-154097603-C-T

Variant names:

• chrX-154097603-C-T
• rs786205048
• NM_001110792.2:c.62+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM6 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.62+1G>A (NM_001110792.2) variant in MECP2 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.62+1G>A variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 15737703) (PM6, PP4). The c.62+1G>A variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the c.62+1G>A variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6, PP4, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274678/MONDO:0010726/016

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 1.69
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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+1G>A		splice_donor intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.-99+1G>A		splice_donor intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.-546+1G>A		splice_donor 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+1G>A		splice_donor intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-99+1G>A		splice_donor intron	N/A	ENSP00000301948.6
	MECP2	ENST00000631210.1	TSL:1	n.305+7178G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 940429 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 293419

African (AFR) AF: 0.00 AC: 0 AN: 20466

American (AMR) AF: 0.00 AC: 0 AN: 20424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14502

East Asian (EAS) AF: 0.00 AC: 0 AN: 22495

South Asian (SAS) AF: 0.00 AC: 0 AN: 35862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 763111

Other (OTH) AF: 0.00 AC: 0 AN: 37931

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	-	Rett syndrome (4)
1	-	-	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	34
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.28	N
PhyloP100		1.7
GERP RS		3.9
PromoterAI		-0.39	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 17
DS_DL_spliceai		0.95		Position offset: 1

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

Other links and lift over

dbSNP: rs786205048; hg19: chrX-153363060;