rs267608406

Variant names:

• chrX-154030648-CGGGCTCAGGTGGAGGTGG-C
• rs267608406
• NM_001110792.2:c.1198_1215delCCACCTCCACCTGAGCCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS2_Supporting BP5 BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro388_Pro393del (NM_004992.3) variant in MECP2 is 0.01% in the African/African American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro388_Pro393del variant is observed in at least 1 unaffected individual (PMID 21160487)(BS2_supporting). The p.Pro388_Pro393del variant is found in a patient with an alternate molecular basis of disease (PMID 21160487)(BP5). In summary, the p.Pro388_Pro393del variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BS2_supporting, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170191/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000097 (0 hom., 3 hem., cov: 0)
  • Exomes 𝑓: 0.000075 (0 hom. 20 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 conservative_inframe_deletion
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 5.37
• 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: Likely_benign. The variant received -6 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.1198_1215delCCACCTCCACCTGAGCCC	p.Pro400_Pro405del	conservative_inframe_deletion	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1162_1179delCCACCTCCACCTGAGCCC	p.Pro388_Pro393del	conservative_inframe_deletion	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.883_900delCCACCTCCACCTGAGCCC	p.Pro295_Pro300del	conservative_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.1198_1215delCCACCTCCACCTGAGCCC	p.Pro400_Pro405del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1162_1179delCCACCTCCACCTGAGCCC	p.Pro388_Pro393del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1162_1179delCCACCTCCACCTGAGCCC	p.Pro388_Pro393del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000968 AC: 7 AN: 72333 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000408 AC: 7 AN: 171619 AF XY: 0.0000480

Gnomad AFR exome AF: 0.000172

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000519

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000747 AC: 60 AN: 803418 Hom.: 0 AF XY: 0.0000820 AC XY: 20 AN XY: 243984

African (AFR) AF: 0.000207 AC: 4 AN: 19306

American (AMR) AF: 0.0000341 AC: 1 AN: 29311

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11852

East Asian (EAS) AF: 0.00 AC: 0 AN: 13492

South Asian (SAS) AF: 0.0000693 AC: 3 AN: 43263

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2572

European-Non Finnish (NFE) AF: 0.0000819 AC: 52 AN: 634914

Other (OTH) AF: 0.00 AC: 0 AN: 30042

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000968 AC: 7 AN: 72333 Hom.: 0 Cov.: 0 AF XY: 0.000187 AC XY: 3 AN XY: 16021

African (AFR) AF: 0.0000558 AC: 1 AN: 17925

American (AMR) AF: 0.00 AC: 0 AN: 5609

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1974

East Asian (EAS) AF: 0.00 AC: 0 AN: 2197

South Asian (SAS) AF: 0.00 AC: 0 AN: 1144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 144

European-Non Finnish (NFE) AF: 0.000151 AC: 6 AN: 39647

Other (OTH) AF: 0.00 AC: 0 AN: 901

Alfa AF: 0.000108 Hom.: 1

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Rett syndrome (2)
-	-	1	MECP2-related disorder (1)
-	1	-	not provided (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4
Mutation Taster		=167/33	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs267608406; hg19: chrX-153296099;