X-154032556-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001110792.2(MECP2):c.64G>C(p.Glu22Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000922 in 1,084,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 missense, splice_region
• Scores: Splicing: ADA: 0.8999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.83

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39929986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.64G>C	p.Glu22Gln	missense_variant, splice_region_variant	2/3	ENST00000453960.7
MECP2	NM_004992.4	c.28G>C	p.Glu10Gln	missense_variant, splice_region_variant	3/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.64G>C	p.Glu22Gln	missense_variant, splice_region_variant	2/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.28G>C	p.Glu10Gln	missense_variant, splice_region_variant	3/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084804 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 354426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	curation	RettBASE	Nov 15, 2007	- -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 21, 2024	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 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T;T;T;T;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;T;D;T;D;D;D;D;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.81	L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.86	N;N;.;.;.;.;.;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.010	D;D;.;.;.;.;.;.;.
Sift4G	Benign	0.20	T;D;T;D;.;T;T;.;.
Polyphen		0.99	D;D;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.081		Gain of methylation at K12 (P = 0.0699);.;Gain of methylation at K12 (P = 0.0699);.;Gain of methylation at K12 (P = 0.0699);.;.;Gain of methylation at K12 (P = 0.0699);Gain of methylation at K12 (P = 0.0699);
MVP		0.98
ClinPred		0.88	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.77
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: rs61754421; hg19: chrX-153298007;