NM_001110792.2:c.1364C>T

Variant names:

• chrX-154030500-G-A
• rs375101073
• NM_001110792.2:c.1364C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the NM_004992.4:c.1328C>T p.Ala443Val variant in gnomAD v4.1 is 0.00007 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ala443Val variant is observed in at least 2 unaffected individuals (internal data, Labcorp Genetics Inc.) (BS2). The p.Ala443Val variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.492). In the absence of conflicting evidence, this is sufficient evidence to classify the p.Ala443Val variant as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA208615/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000059 (0 hom. 19 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:3
• Conservation: PhyloP100: 5.49
• Publications: 6 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: Likely_benign. The variant received -4 ACMG points.

• 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.1364C>T	p.Ala455Val	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1328C>T	p.Ala443Val	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.1049C>T	p.Ala350Val	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.1364C>T	p.Ala455Val	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1328C>T	p.Ala443Val	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1328C>T	p.Ala443Val	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111634 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183399 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000592 AC: 65 AN: 1098209 Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 19 AN XY: 363575

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000772 AC: 65 AN: 842130

Other (OTH) AF: 0.00 AC: 0 AN: 46097

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111634 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33782

African (AFR) AF: 0.00 AC: 0 AN: 30701

American (AMR) AF: 0.00 AC: 0 AN: 10570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53037

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	-	1	Rett syndrome (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.49
Sift	Benign	0.082	T
Sift4G	Benign	0.36	T
Polyphen		0.041	B
Vest4		0.31
MVP		1.0
ClinPred		0.21	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.16
gMVP		0.49
Mutation Taster		=91/9	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: rs375101073; hg19: chrX-153295951;