X-154097642-CGCGGCGGCG-CGCG

Variant names:

• chrX-154097642-CGCGGCG-C
• rs398123566
• NM_001110792.2:c.18_23delCGCCGC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.18_23delCGCCGC​(p.Ala7_Ala8del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000381 in 1,024,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign. The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.000036 (0 hom. 4 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 4.00
• Publications: 3 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001110792.2
• BP6: Variant X-154097642-CGCGGCG-C is Benign according to our data. Variant chrX-154097642-CGCGGCG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 156657.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd4 at 6 XL,Unknown,AD gene.

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.18_23delCGCCGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.-143_-138delCGCCGC		5_prime_UTR	Exon 1 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-590_-585delCGCCGC		5_prime_UTR	Exon 1 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.18_23delCGCCGC	p.Ala7_Ala8del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-143_-138delCGCCGC		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000631210.1	TSL:1	n.305+7133_305+7138delCGCCGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000563 AC: 6 AN: 106552 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000307

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000197

Gnomad OTH AF: 0.000695

GnomAD2 exomes AF: 0.00 AC: 0 AN: 59976 AF XY: 0.00

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: 0.0000360 AC: 33 AN: 917924 Hom.: 0 AF XY: 0.0000140 AC XY: 4 AN XY: 284702

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000202 AC: 4 AN: 19832

American (AMR) AF: 0.0000585 AC: 1 AN: 17095

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13264

East Asian (EAS) AF: 0.00 AC: 0 AN: 22366

South Asian (SAS) AF: 0.0000315 AC: 1 AN: 31738

European-Finnish (FIN) AF: 0.0000463 AC: 1 AN: 21607

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3231

European-Non Finnish (NFE) AF: 0.0000332 AC: 25 AN: 751915

Other (OTH) AF: 0.0000271 AC: 1 AN: 36876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000345798), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000563 AC: 6 AN: 106585 Hom.: 0 Cov.: 21 AF XY: 0.0000992 AC XY: 3 AN XY: 30233

African (AFR) AF: 0.000101 AC: 3 AN: 29735

American (AMR) AF: 0.00 AC: 0 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2596

East Asian (EAS) AF: 0.000308 AC: 1 AN: 3243

South Asian (SAS) AF: 0.00 AC: 0 AN: 2490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5017

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 209

European-Non Finnish (NFE) AF: 0.0000197 AC: 1 AN: 50872

Other (OTH) AF: 0.000686 AC: 1 AN: 1457

Alfa AF: 0.00 Hom.: 4

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Rett syndrome (2)
-	1	-	MECP2-related disorder (1)
-	-	1	not specified (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)
-	1	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0

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: rs398123566;

hg19: chrX-153363099;

COSMIC: COSV105884117;

COSMIC: COSV105884117;