rs61750243

chrX-154031013-G-AchrX-154031013-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):c.851C>T(p.Pro284Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000752 in 1,210,529 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P284R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.000074 (0 hom. 28 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.29

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 Benign. Variant got -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, phyloP100way_vertebrate [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.32860392).
• BP6: Variant X-154031013-G-A is Benign according to our data. Variant chrX-154031013-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031013-G-A is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.851C>T	p.Pro284Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.815C>T	p.Pro272Leu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.851C>T	p.Pro284Leu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.815C>T	p.Pro272Leu	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000891 AC: 10 AN: 112290 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34466

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.000325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000769 AC: 14 AN: 182162 Hom.: 0 AF XY: 0.000119 AC XY: 8 AN XY: 67384

Gnomad AFR exome AF: 0.0000787

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000738 AC: 81 AN: 1098188 Hom.: 0 Cov.: 35 AF XY: 0.0000770 AC XY: 28 AN XY: 363562

Gnomad4 AFR exome AF: 0.0000757

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000772

Gnomad4 OTH exome AF: 0.000108

GnomAD4 genome AF: 0.0000890 AC: 10 AN: 112341 Hom.: 0 Cov.: 23 AF XY: 0.000174 AC XY: 6 AN XY: 34527

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000365

Gnomad4 FIN AF: 0.000325

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000143 Hom.: 2

Bravo AF: 0.0000567

ExAC AF: 0.0000742 AC: 9

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	curation	RettBASE	Mar 10, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2013	- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Rett syndrome Benign:1

Benign, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2018

This variant is associated with the following publications: (PMID: 16376510, 17387578) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.46
MVP		0.99
ClinPred		0.15	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.47
gMVP		0.93

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: rs61750243; hg19: chrX-153296464; COSMIC: COSV57655170; COSMIC: COSV57655170;