rs267608557

Variant names:

• chrX-154030836-T-C
• rs267608557
• NM_001110792.2:c.1028A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP4 PM2_Supporting BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_004992.4:c.992A>G (p.Lys331Arg) variant in MECP2 has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PMID:21212452) (PP4) and in at least 1 unaffected individual (PMID:21212452) (BS2_Supporting). The p.Lys331Arg variant in MECP2 is absent from gnomAD v4.1 (PM2_Supporting). Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.459). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Rett syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Rett and Angelman-like disorders VCEP (BS2_Supporting, PM2_Supporting, PP4) (MECP2 Specifications v3.0; curation approved on 2/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170424/MONDO:0010726/036

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 1.29
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.1028A>G	p.Lys343Arg	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.992A>G	p.Lys331Arg	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.713A>G	p.Lys238Arg	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.1028A>G	p.Lys343Arg	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.992A>G	p.Lys331Arg	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.992A>G	p.Lys331Arg	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Rett syndrome (2)
-	-	1	not specified (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.46
Sift	Benign	0.038	D
Sift4G	Benign	0.66	T
Polyphen		0.40	B
Vest4		0.20
MutPred		0.18		Loss of ubiquitination at K331 (P = 0.0341)
MVP		0.94
ClinPred		0.46	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.71
Mutation Taster		=95/5	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: rs267608557; hg19: chrX-153296287;