rs61750240

Variant names:

• chrX-154031020-G-A
• rs61750240
• NM_001110792.2:c.844C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031020-G-A
• chrX-154031020-G-C
• chrX-154031020-G-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.844C>T​(p.Arg282*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000698544: Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression.; SCV000967749: Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yusufzai and Wollfe 2000, Delepine et al. 2013).; SCV002107116: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:11058114; 23238081) - PS3_moderate."; SCV004046997: Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013).; SCV000191047: Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); PMID:26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587; SCV000885680: Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000).; SCV000544624: Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID:11058114, 23238081).; SCV000741795: Another study found that this mutation is unable to repress transcription, a major function of MeCP2 protein (Yusufzai TM et al. Nucleic Acids Res. 2000;28(21):4172-4179).; SCV004814155: In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013).". Synonymous variant affecting the same amino acid position (i.e. R282R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:48 O:1
• Conservation: PhyloP100: 2.94
• Publications: 243 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 406 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000698544: Functional studies have shown that this nonsense mutation produced a protein that is defective in transcription repression.; SCV000967749: Functional studies, including a mouse model with this variant, support that p.Arg270X impacts protein function (Baker et al. 2013, Yusufzai and Wollfe 2000, Delepine et al. 2013).; SCV002107116: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11058114; 23238081) - PS3_moderate."; SCV004046997: Experimental studies have shown that this nonsense change impairs microtubule stability and the ability of the MECP2 protein to repress transcription (Yusufzai T.M. and Wolffe A.P., 2000; Delépine C et. al., 2013).; SCV000191047: Located in the transcriptional repression domain (TRD) and functional studies indicate this variant impairs the stability of the MECP2 protein and affects its ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); PMID: 26175308, 18174548, 10767337, 19914908, 18337588, 10854091, 11313764, 10814718, 11896459, 22982301, 11058114, 20625242, 23238081, 27255190, 15287421, 23270700, 28831199, 16077729, 17914728, 29655203, 30536762, 30417326, 31088393, 31095231, 23452848, 31618753, 32105570, 33767182, 33726816, 32472557, 34177756, 33994118, 12030010, 32959227, 33258288, 31031587; SCV000885680: Functional characterization of the truncated protein indicates loss of specificity for methylated DNA, and impaired repressive functions (Yusufzai 2000).; SCV000544624: Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081).; SCV000741795: Another study found that this mutation is unable to repress transcription, a major function of MeCP2 protein (Yusufzai TM et al. Nucleic Acids Res. 2000;28(21):4172-4179).; SCV004814155: In functional studies, the variant has been shown to exhibit reduced stability; to disrupt transcriptional repression, DNA binding, and nucleosome interactions; to result in mislocalization of the chromatin remodeling protein ATRX; and to have a dominant-negative effect on microtubule stability (Yusufzai et al. 2000; Delépine et al. 2013; Baker et al. 2013).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031020-G-A is Pathogenic according to our data. Variant chrX-154031020-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.844C>T	p.Arg282*	stop_gained	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.808C>T	p.Arg270*	stop_gained	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.529C>T	p.Arg177*	stop_gained	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.844C>T	p.Arg282*	stop_gained	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.808C>T	p.Arg270*	stop_gained	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.808C>T	p.Arg270*	stop_gained	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
25	-	-	Rett syndrome (26)
14	-	-	not provided (14)
2	-	-	MECP2-related disorder (2)
2	-	-	Severe neonatal-onset encephalopathy with microcephaly (2)
1	-	-	Autism, susceptibility to, X-linked 3 (1)
1	-	-	Encephalopathy, neonatal severeMental retardation, X-linked, syndromic 13Rett syndrome (1)
1	-	-	Inborn genetic diseases (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	-	-	Syndromic X-linked intellectual disability Lubs type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		2.9
Vest4		0.96
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61750240; hg19: chrX-153296471; COSMIC: COSV57657683; COSMIC: COSV57657683;