rs61753008

Variant names:

• chrX-154030654-CAGGTGG-C
• rs61753008
• NM_001110792.2:c.1204_1209delCCACCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PM1 PM4 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.1204_1209delCCACCT​(p.Pro402_Pro403del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000144 in 1,169,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 49 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P402P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.00014 (0 hom. 48 hem.)
• Consequence: MECP2 NM_001110792.2 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.01
• Publications: 4 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

Our verdict: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 18 uncertain in NM_001110792.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2.
• BP6: Variant X-154030654-CAGGTGG-C is Benign according to our data. Variant chrX-154030654-CAGGTGG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 12 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.1204_1209delCCACCT	p.Pro402_Pro403del	conservative_inframe_deletion	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1168_1173delCCACCT	p.Pro390_Pro391del	conservative_inframe_deletion	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.889_894delCCACCT	p.Pro297_Pro298del	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.1204_1209delCCACCT	p.Pro402_Pro403del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1168_1173delCCACCT	p.Pro390_Pro391del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1168_1173delCCACCT	p.Pro390_Pro391del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 12 AN: 90582 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000506

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000108

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000635 AC: 11 AN: 173240 AF XY: 0.0000788

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: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 156 AN: 1079130 Hom.: 0 AF XY: 0.000137 AC XY: 48 AN XY: 350942

African (AFR) AF: 0.0000765 AC: 2 AN: 26154

American (AMR) AF: 0.00 AC: 0 AN: 34807

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19213

East Asian (EAS) AF: 0.00 AC: 0 AN: 29894

South Asian (SAS) AF: 0.0000566 AC: 3 AN: 52983

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3629

European-Non Finnish (NFE) AF: 0.000174 AC: 145 AN: 831110

Other (OTH) AF: 0.000132 AC: 6 AN: 45306

GnomAD4 genome AF: 0.000132 AC: 12 AN: 90585 Hom.: 0 Cov.: 0 AF XY: 0.0000469 AC XY: 1 AN XY: 21323

African (AFR) AF: 0.000218 AC: 5 AN: 22932

American (AMR) AF: 0.000129 AC: 1 AN: 7725

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2368

East Asian (EAS) AF: 0.00 AC: 0 AN: 3105

South Asian (SAS) AF: 0.000510 AC: 1 AN: 1960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.000108 AC: 5 AN: 46497

Other (OTH) AF: 0.00 AC: 0 AN: 1162

Alfa AF: 0.000285 Hom.: 2

Bravo AF: 0.000106

Asia WGS AF: 0.000398 AC: 1 AN: 2521

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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		5.0
Mutation Taster		=161/39	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61753008; hg19: chrX-153296105;