X-154031355-G-T

Position:

• chrX-154031355-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000453960.7(MECP2):​c.509C>A​(p.Thr170Lys) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T170A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.45

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 10 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000453960.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154031356-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 143590.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant X-154031355-G-T is Pathogenic according to our data. Variant chrX-154031355-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1501953.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.509C>A	p.Thr170Lys	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.473C>A	p.Thr158Lys	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.509C>A	p.Thr170Lys	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.473C>A	p.Thr158Lys	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2022

ClinVar contains an entry for this variant (Variation ID: 1501953). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 158 of the MECP2 protein (p.Thr158Lys). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MECP2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr158 amino acid residue in MECP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11738866, 12843318, 18337588, 23421866). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.80	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D;D;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0090	D;D;.;.;.
Sift4G	Benign	0.11	T;T;.;T;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.79
MutPred		0.64		Gain of methylation at T158 (P = 4e-04);.;Gain of methylation at T158 (P = 4e-04);.;.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153296806;