rs1557135593

chrX-154030653-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001110792.2(MECP2):c.1211A>C(p.Glu404Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E404D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 19)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22795776).
• BP6: Variant X-154030653-T-G is Benign according to our data. Variant chrX-154030653-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536582.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1211A>C	p.Glu404Ala	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1175A>C	p.Glu392Ala	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1211A>C	p.Glu404Ala	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1175A>C	p.Glu392Ala	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*547A>C		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*547A>C		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 19

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2020

The p.E392A variant (also known as c.1175A>C), located in coding exon 3 of the MECP2 gene, results from an A to C substitution at nucleotide position 1175. The glutamic acid at codon 392 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.55	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.54	T;T
Polyphen		0.23	B;B
Vest4		0.27
MutPred		0.19		Gain of glycosylation at S395 (P = 0.1873);.;
MVP		0.88
ClinPred		0.14	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557135593; hg19: chrX-153296104;