rs267608328

chrX-154030398-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BP6_Strong

The NM_001110792.2(MECP2):c.1466G>C(p.Ser489Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000728 in 1,098,234 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. S489S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 4.99

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08768356).
• BP6: Variant X-154030398-C-G is Benign according to our data. Variant chrX-154030398-C-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 143475.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chrX-154030398-C-G is described in Lovd as [Pathogenic]. Variant chrX-154030398-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1466G>C	p.Ser489Thr	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1430G>C	p.Ser477Thr	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1466G>C	p.Ser489Thr	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1430G>C	p.Ser477Thr	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000628176.2	c.*802G>C		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098234 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 3 AN XY: 363588

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: 0.00000950

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 13, 2021	The p.Ser477Thr (NM_004992.3) variant is observed in at least 2 unaffected individuals (PMID 12655490)(BS2). The p.Ser477Thr variant is observed in the MECP2 gene where a second pathogenic variant in the same gene is present in the patient (PMID 12655490); however, it is unknown if the variants are in cis or trans (BP5 - not met). The p.Ser477Thr variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Ser477Thr variant in MECP2 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (BS2, PM2_supporting). -
Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 14, 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: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2).PMID: 12655490 This variant is absent from gnomAD (PM2_Supporting). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Nov 01, 2007

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Benign	0.79
DEOGEN2	Benign	0.31	T;.
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.11	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.76	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.34	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0090	B;B
Vest4		0.067
MutPred		0.22		Gain of glycosylation at S477 (P = 0.2535);.;
MVP		0.94
ClinPred		0.57	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.27

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: rs267608328; hg19: chrX-153295849;