X-154030661-AGGTGGGG-AG

Variant names:

• chrX-154030661-AGGTGGG-A
• rs267608332
• NM_001110792.2:c.1197_1202delCCCACC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: The p.Pro390_Pro391del variant in MECP2 (NM_004992.3) has been reported in an individual with intellectual disability (PMID 21982064). The allele frequency of the p.Pro390_Pro391del variant in MECP2 is 0.1158% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Pro390_Pro391del variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID:23696494) (BP2). In summary, the p.Pro390_Pro391del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA232911/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.000069 (0 hom. 15 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:4 O:1
• Conservation: PhyloP100: 3.20
• 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: 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 -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1197_1202delCCCACC	p.Pro400_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1161_1166delCCCACC	p.Pro388_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.882_887delCCCACC	p.Pro295_Pro296del	disruptive_inframe_deletion	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1197_1202delCCCACC	p.Pro400_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1161_1166delCCCACC	p.Pro388_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1161_1166delCCCACC	p.Pro388_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000609 AC: 1 AN: 16414 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00267

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 16 AN: 132529 AF XY: 0.000143

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 37 AN: 535637 Hom.: 0 AF XY: 0.0000957 AC XY: 15 AN XY: 156659

African (AFR) AF: 0.00 AC: 0 AN: 13489

American (AMR) AF: 0.00 AC: 0 AN: 17484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7694

East Asian (EAS) AF: 0.000255 AC: 2 AN: 7836

South Asian (SAS) AF: 0.00126 AC: 28 AN: 22278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13189

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1775

European-Non Finnish (NFE) AF: 0.0000115 AC: 5 AN: 432938

Other (OTH) AF: 0.000106 AC: 2 AN: 18954

GnomAD4 genome AF: 0.0000609 AC: 1 AN: 16414 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4652

African (AFR) AF: 0.00 AC: 0 AN: 3899

American (AMR) AF: 0.00 AC: 0 AN: 1398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 448

East Asian (EAS) AF: 0.00 AC: 0 AN: 763

South Asian (SAS) AF: 0.00267 AC: 1 AN: 374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8681

Other (OTH) AF: 0.00 AC: 0 AN: 209

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Rett syndrome (2)
-	1	-	Angelman syndrome (1)
-	-	1	not provided (2)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=151/49	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs267608332; hg19: chrX-153296112;