rs782174572

Variant names:

• chrX-154030661-AGGTGGGGGCAGG-A
• rs782174572
• NM_001110792.2:c.1191_1202delCCTGCCCCCACC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP5 BS1 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Leu386_Pro389del variant in MECP2 (NM_004992.3) is 0.019% in Latino/Admixed 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.Leu386_Pro389del variant is observed in 3 unaffected individuals (internal database) (BS2). The p.Leu386_Pro389del variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). The p.Leu386_Pro389del variant has been observed in 2 individuals with neurological disorders (PMID:19914908, 23262346) (PS4 not met). In summary, the p.Leu386_Pro389del variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274655/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., 4 hem., cov: 0)
  • Exomes 𝑓: 0.000063 (0 hom. 4 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• 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), Ambry Genetics, Orphanet, G2P, ClinGen
• 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.

• 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.1191_1202delCCTGCCCCCACC	p.Leu398_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1155_1166delCCTGCCCCCACC	p.Leu386_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.876_887delCCTGCCCCCACC	p.Leu293_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.1191_1202delCCTGCCCCCACC	p.Leu398_Pro401del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1155_1166delCCTGCCCCCACC	p.Leu386_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1155_1166delCCTGCCCCCACC	p.Leu386_Pro389del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000426 AC: 7 AN: 16414 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000513

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: 0.000576

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000679 AC: 9 AN: 132529 AF XY: 0.0000408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000190

Gnomad ASJ exome AF: 0.000180

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000635 AC: 34 AN: 535603 Hom.: 0 AF XY: 0.0000255 AC XY: 4 AN XY: 156629

African (AFR) AF: 0.00 AC: 0 AN: 13486

American (AMR) AF: 0.000172 AC: 3 AN: 17484

Ashkenazi Jewish (ASJ) AF: 0.000130 AC: 1 AN: 7694

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

South Asian (SAS) AF: 0.0000898 AC: 2 AN: 22278

European-Finnish (FIN) AF: 0.0000758 AC: 1 AN: 13189

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

European-Non Finnish (NFE) AF: 0.0000554 AC: 24 AN: 432908

Other (OTH) AF: 0.0000528 AC: 1 AN: 18953

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000426 AC: 7 AN: 16414 Hom.: 0 Cov.: 0 AF XY: 0.000860 AC XY: 4 AN XY: 4652

African (AFR) AF: 0.000513 AC: 2 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: 0.00 AC: 0 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: 0.000576 AC: 5 AN: 8681

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Rett syndrome (3)
-	-	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		3.2
Mutation Taster		=168/32	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs782174572;

hg19: chrX-153296112;