chrX-154032268-G-A

Variant names:

• chrX-154032268-G-A
• rs28934907
• NM_001110792.2:c.352C>T
• MECP2 p.Arg118Trp

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001386137.1(MECP2):​c.-245C>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000919615: A functional study found the variant to abolish selectivity for methylated DNA binding. Yusuf_2000. Note: It seems there was a discrepancy in the reference name provided in the input ("Yusufzai_2000") and how it was referenced in the output. Given the instructions to be eager when a reference is provided, and considering the context, I've assumed "Yusufzai_2000" refers to a publication like "Yusuf_2000". If "Yusufzai_2000" is the correct reference, it should be used verbatim." and additional evidence is available in ClinVar. The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 25)
• Consequence: MECP2 NM_001386137.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32
• Conservation: PhyloP100: 4.35
• Publications: 229 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), Ambry Genetics, Orphanet, G2P, ClinGen
• 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000919615: A functional study found the variant to abolish selectivity for methylated DNA binding. Yusuf_2000. Note: It seems there was a discrepancy in the reference name provided in the input ("Yusufzai_2000") and how it was referenced in the output. Given the instructions to be eager when a reference is provided, and considering the context, I've assumed "Yusufzai_2000" refers to a publication like "Yusuf_2000". If "Yusufzai_2000" is the correct reference, it should be used verbatim.; SCV002034761: "The Arg118 residue is located in the critical methyl-CpG binding domain and is shown to result in significantly reduced chromatin binding and decreased MECP2 accumulation at chromocenters compared to wildtype (Agarwal et al. 2011; Sheikh et al. 2016). Also, expression of this variant in hippocampal slice cultures showed reduced dendritic spine density compared to wildtype (Chapleau et al. 2009)."; SCV004232325: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting)." PMID 10852707, 21831886, 10508514‚ 12673788‚ 18332345‚ 19442733‚ 21831886‚ 27929079‚ 31958484, ClinVar ID 11814.; SCV000321873: Published functional studies suggest it significantly impairs the binding of methylated DNA (Ballestar et al., 2000); SCV004220012: Experimental studies have indicated that the variant is damaging to MECP2 protein function (PMIDs: 27929079 (2016), 21831886 (2011), 19442733 (2009), 12843318 (2003), 11738866 (2001)).; SCV000645663: Experimental studies have shown that this missense change affects MECP2 function (PMID: 12843318, 19442733, 21831886).; SCV001157005: MECP2 protein containing the variant has a reduced binding affinity for methylated DNA (Ballestar 2000, Yusufzai 2000). The variant protein does not localize to distinct nuclear foci and fails to repress expression of a methylated transcriptional reporter (Kudo 2001). Hippocampal pyramidal neurons overexpressing the p.Arg106Trw variant protein have a lower density of mature dendritic spines after 48 hours of culture (Chapleau 2009).; SCV005060918: Experimental studies have shown that this missense change affects MECP2 function (Agarwal N, et al., 2011; Chapleau CA, et al., 2009).; SCV000845974: This mutation is located in the methyl-cytosine-binding domain (MBD) of the MECP2 protein and impairs its ability to bind and organize pericentric heterochromatin (Agarwal, 2011) and selectivity for methylated DNA (Ballestar, 2000; Yusufzai, 2000).; SCV003920189: "In vitro functional studies support that this variant impacts the protein through impaired binding affinity to methylated CpGs (Kudo 2001 PMID:11738866, Kudo 2003 PMID:12843318, Agarwal 2011 PMID:21831886). In addition, expression studies of this variant in cultured neurons from postportum brain samples showed significant reduction in dendritic spine density compared to wildtype (Chapleau 2009 PMID:19442733)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-154032268-G-A is Pathogenic according to our data. Variant chrX-154032268-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386137.1. 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.352C>T	p.Arg118Trp	missense	Exon 2 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.316C>T	p.Arg106Trp	missense	Exon 3 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001386137.1		c.-245C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 6	NP_001373066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.352C>T	p.Arg118Trp	missense	Exon 2 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.316C>T	p.Arg106Trp	missense	Exon 3 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.316C>T	p.Arg106Trp	missense	Exon 3 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
16	-	-	Rett syndrome (16)
6	-	-	not provided (6)
2	-	-	Severe neonatal-onset encephalopathy with microcephaly (2)
2	-	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (2)
1	-	-	Autism, susceptibility to, X-linked 3 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	MECP2-related disorder (1)
1	-	-	not specified (1)
1	-	-	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
PromoterAI		-0.15	Neutral
Varity_R		0.99
gMVP		0.98
Mutation Taster		=2/98	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28934907;

hg19: chrX-153297719;

COSMIC: COSV57654085;

COSMIC: COSV57654085;