rs786205892

Positions:

• chrX-154092209-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004992.4(MECP2):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: MECP2 NM_004992.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.36

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154092209-T-A is Pathogenic according to our data. Variant chrX-154092209-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 192289.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_004992.4	c.1A>T	p.Met1?	start_lost	2/4	ENST00000303391.11
MECP2	NM_001110792.2	c.62+5395A>T		intron_variant		ENST00000453960.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.1A>T	p.Met1?	start_lost	2/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.62+5395A>T		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.26	T;T;T;T;.
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;N;N
PROVEAN	Benign	-0.45	N;.;.;D;.
REVEL	Uncertain	0.54
Sift	Benign	0.14	T;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.
Polyphen		0.0020	B;.;.;.;.
Vest4		0.85
MutPred		0.97		Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);Loss of solvent accessibility (P = 0.0595);
MVP		1.0
ClinPred		0.62	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		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: rs786205892; hg19: chrX-153357667;