rs267608533

chrX-154030971-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001110792.2(MECP2):c.893A>G(p.Lys298Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,098,217 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.25

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 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 11 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28110513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.893A>G	p.Lys298Arg	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.857A>G	p.Lys286Arg	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.893A>G	p.Lys298Arg	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.857A>G	p.Lys286Arg	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098217 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 1 AN XY: 363579

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: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 15, 2011	- -

Rett syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Jan 15, 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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.97	L;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N;N;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D;D;.
Sift4G	Benign	0.85	T;T;T
Polyphen		0.14	B;B;.
Vest4		0.12
MutPred		0.12		Loss of methylation at K286 (P = 0.0262);.;.;
MVP		0.97
ClinPred		0.41	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.36
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267608533; hg19: chrX-153296422;