chrX-154030664-TGGG-T

Variant names:

• chrX-154030664-TGGG-T
• rs267608339
• NM_001110792.2:c.1197_1199delCCC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PM4_Supporting BP6 BS2

The NM_001110792.2(MECP2):​c.1197_1199delCCC​(p.Pro400del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 705,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 3.20
• Publications: 9 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 21 benign, 17 uncertain in NM_001110792.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001110792.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-154030664-TGGG-T is Benign according to our data. Variant chrX-154030664-TGGG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 143389.
• BS2: High AC in GnomAdExome4 at 7 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.1197_1199delCCC	p.Pro400del	disruptive_inframe_deletion	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1161_1163delCCC	p.Pro388del	disruptive_inframe_deletion	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.882_884delCCC	p.Pro295del	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.1197_1199delCCC	p.Pro400del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1161_1163delCCC	p.Pro388del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1161_1163delCCC	p.Pro388del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000935 AC: 2 AN: 21381 Hom.: 0 Cov.: 20

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: 0.000178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000150 AC: 2 AN: 133195 AF XY: 0.0000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000102 AC: 7 AN: 684074 Hom.: 0 AF XY: 0.0000148 AC XY: 3 AN XY: 202488

African (AFR) AF: 0.00 AC: 0 AN: 16441

American (AMR) AF: 0.00 AC: 0 AN: 16924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8553

East Asian (EAS) AF: 0.000202 AC: 2 AN: 9912

South Asian (SAS) AF: 0.00 AC: 0 AN: 26843

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13873

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1973

European-Non Finnish (NFE) AF: 0.00000884 AC: 5 AN: 565388

Other (OTH) AF: 0.00 AC: 0 AN: 24167

GnomAD4 genome AF: 0.0000935 AC: 2 AN: 21381 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 5863

African (AFR) AF: 0.00 AC: 0 AN: 5169

American (AMR) AF: 0.00 AC: 0 AN: 1840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 599

East Asian (EAS) AF: 0.00 AC: 0 AN: 937

South Asian (SAS) AF: 0.00 AC: 0 AN: 478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 663

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.000178 AC: 2 AN: 11244

Other (OTH) AF: 0.00 AC: 0 AN: 253

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (2)
-	-	1	not specified (1)
-	-	1	Rett syndrome (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		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267608339; hg19: chrX-153296115;