rs786205016

Positions:

• chrX-154031397-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000453960.7(MECP2):​c.467A>G​(p.Lys156Arg) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.86

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000453960.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.467A>G	p.Lys156Arg	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.431A>G	p.Lys144Arg	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.467A>G	p.Lys156Arg	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.431A>G	p.Lys144Arg	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: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Aug 14, 2023

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria.Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting). Computational prediction analysis tools suggests a deleterious impact (REVEL score ≥ 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Dec 05, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;T;D;D;T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D;D;T;T;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N;N;.;N;.;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.019	D;D;.;T;.;.;.
Sift4G	Uncertain	0.031	D;D;D;D;.;T;D
Polyphen		0.99	D;D;.;.;.;.;.
Vest4		0.27
MutPred		0.42		Loss of methylation at K144 (P = 0.0099);.;Loss of methylation at K144 (P = 0.0099);.;Loss of methylation at K144 (P = 0.0099);.;.;
MVP		0.99
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.73
gMVP		0.78

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: rs786205016; hg19: chrX-153296848;