rs28934908

Variant names:

• chrX-154031409-G-A
• rs28934908
• NM_001110792.2:c.455C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031409-G-A
• chrX-154031409-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001110792.2(MECP2):​c.455C>T​(p.Ala152Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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: "SCV003923342: Experimental study by Agarwal N, et al., 2011 showed MECP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, and their dysfunction lead to Rett syndrome." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A152A) has been classified as Likely benign. The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34 O:1
• Conservation: PhyloP100: 9.46
• Publications: 87 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003923342: Experimental study by Agarwal N, et al., 2011 showed MECP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, and their dysfunction lead to Rett syndrome.; SCV001423701: "This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3]"; SCV005418117: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005360864: "In vitro functional studies demonstrate this variant affects MECP2 function (Nan et al. 2007. PubMed ID: 17296936; Sheikh et al. 2016. PubMed ID: 27929079)"
• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant X-154031409-G-A is Pathogenic according to our data. Variant chrX-154031409-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11823.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.455C>T	p.Ala152Val	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.419C>T	p.Ala140Val	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.140C>T	p.Ala47Val	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.455C>T	p.Ala152Val	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.419C>T	p.Ala140Val	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.419C>T	p.Ala140Val	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097434 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 1 AN XY: 362798

African (AFR) AF: 0.0000379 AC: 1 AN: 26381

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841410

Other (OTH) AF: 0.00 AC: 0 AN: 46073

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	not provided (10)
6	-	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (6)
4	-	-	Rett syndrome (5)
2	-	-	Intellectual disability (2)
2	-	-	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 (2)
2	-	-	Syndromic X-linked intellectual disability Lubs type (2)
1	-	-	Atypical behavior (1)
1	-	-	Autism, susceptibility to, X-linked 3 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	MECP2-related disorder (1)
1	-	-	Micrognathia;C0395837:Stenosis of the external auditory canal;C0423110:Downslanted palpebral fissures;C1384666:Hearing impairment;C1854301:Motor delay;C1859778:Postnatal growth retardation;C3714756:Intellectual disability;C4551563:Microcephaly (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome (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	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.91
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.83		Loss of helix (P = 0.079)
MVP		1.0
ClinPred		0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.86
Mutation Taster		=15/85	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: rs28934908; hg19: chrX-153296860; COSMIC: COSV57653043; COSMIC: COSV57653043;