NM_001110792.2:c.52G>A

Variant names:

• chrX-154097614-C-T
• rs1234894476
• NM_001110792.2:c.52G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001110792.2(MECP2):​c.52G>A​(p.Glu18Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 107,612 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E18D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000019 (0 hom., 1 hem., cov: 21)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.80
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.52G>A	p.Glu18Lys	missense	Exon 1 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.-109G>A		5_prime_UTR	Exon 1 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.-556G>A		5_prime_UTR	Exon 1 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.52G>A	p.Glu18Lys	missense	Exon 1 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-109G>A		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6
	MECP2	ENST00000631210.1	TSL:1	n.305+7167G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000186 AC: 2 AN: 107612 Hom.: 0 Cov.: 21

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: 0.0000391

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome AF: 0.0000186 AC: 2 AN: 107612 Hom.: 0 Cov.: 21 AF XY: 0.0000326 AC XY: 1 AN XY: 30642

African (AFR) AF: 0.00 AC: 0 AN: 29891

American (AMR) AF: 0.00 AC: 0 AN: 10478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2604

East Asian (EAS) AF: 0.00 AC: 0 AN: 3298

South Asian (SAS) AF: 0.00 AC: 0 AN: 2549

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5337

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0000391 AC: 2 AN: 51131

Other (OTH) AF: 0.00 AC: 0 AN: 1473

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MECP2 c.-109G>A is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 25723 control chromosomes (ExAC), though control data is limited because of the distance of the variant from the coding region. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-109G>A in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

Inborn genetic diseases Uncertain:1

Jul 15, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.54	D
PhyloP100		1.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.40
Sift	Benign	0.087	T
Sift4G	Benign	0.27	T
Polyphen		0.93	P
Vest4		0.39
MutPred		0.15		Gain of ubiquitination at E18 (P = 0.0051)
MVP		0.93
ClinPred		0.98	D
GERP RS		3.9
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
gMVP		0.46
Mutation Taster		=88/12	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: rs1234894476; hg19: chrX-153363071;