rs61752381

Variant names:

• chrX-154030721-ATGGTGG-A
• rs61752381
• NM_001110792.2:c.1137_1142delCCACCA

Your query was ambiguous. Multiple possible variants found:

• chrX-154030721-ATGGTGG-A
• chrX-154030721-ATGGTGG-ATGG
• chrX-154030721-ATGGTGG-ATGGTGGTGG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1 PM2 BP3 BP6_Very_Strong

The NM_001110792.2(MECP2):​c.1137_1142delCCACCA​(p.His380_His381del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,203,593 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. H379H) has been classified as Likely benign. The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 3.28
• 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 -5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 17 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001110792.2
• BP6: Variant X-154030721-ATGGTGG-A is Benign according to our data. Variant chrX-154030721-ATGGTGG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 156614.Status of the report is reviewed_by_expert_panel, 3 stars.

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.1137_1142delCCACCA	p.His380_His381del	disruptive_inframe_deletion	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1101_1106delCCACCA	p.His368_His369del	disruptive_inframe_deletion	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.822_827delCCACCA	p.His275_His276del	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.1137_1142delCCACCA	p.His380_His381del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1101_1106delCCACCA	p.His368_His369del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1101_1106delCCACCA	p.His368_His369del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000185 AC: 2 AN: 107888 Hom.: 0 Cov.: 22

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000387

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095705 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 361511

African (AFR) AF: 0.00 AC: 0 AN: 26314

American (AMR) AF: 0.00 AC: 0 AN: 35078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3985

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840712

Other (OTH) AF: 0.00 AC: 0 AN: 45979

GnomAD4 genome AF: 0.0000185 AC: 2 AN: 107888 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 30790

African (AFR) AF: 0.00 AC: 0 AN: 29444

American (AMR) AF: 0.00 AC: 0 AN: 10233

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2578

East Asian (EAS) AF: 0.00 AC: 0 AN: 3434

South Asian (SAS) AF: 0.00 AC: 0 AN: 2438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000387 AC: 2 AN: 51708

Other (OTH) AF: 0.00 AC: 0 AN: 1455

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs61752381; hg19: chrX-153296172;