NM_001110792.2:c.535C>T

Variant names:

• chrX-154031329-G-A
• rs61748420
• NM_001110792.2:c.535C>T

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PS2 PM2_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The p.Arg167Trp variant (NM_004992.3) in MECP2 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with MECP2-related disorders through testing completed at GeneDx (PS2_very strong). The variant has been reported to segregate in at least five informative meioses in published literature (Couvert et al., 2001) (PP1_strong). The p.Arg167Trp variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Arg167Trp variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PS2_very strong, PP1_strong, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170308/MONDO:0010726/016

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:2
• Conservation: PhyloP100: 7.48
• Publications: 25 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: Pathogenic. The variant received 9 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.535C>T	p.Arg179Trp	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.499C>T	p.Arg167Trp	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.220C>T	p.Arg74Trp	missense	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.535C>T	p.Arg179Trp	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.499C>T	p.Arg167Trp	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.499C>T	p.Arg167Trp	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098208 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 363562

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842103

Other (OTH) AF: 0.00 AC: 0 AN: 46098

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
4	1	-	Rett syndrome (5)
1	1	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	MECP2-related disorder (1)
1	-	-	See cases (1)
1	-	-	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.84	D
PhyloP100		7.5
Sift4G	Pathogenic	0.0	D
Vest4		0.54
MVP		0.93
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs61748420; hg19: chrX-153296780;