rs61753016

chrX-154030614-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):c.1250C>T(p.Pro417Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,203,207 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P417S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000039 (0 hom. 17 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:6 B:4
• Conservation: PhyloP100: 4.66

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34277403).
• BP6: Variant X-154030614-G-A is Benign according to our data. Variant chrX-154030614-G-A is described in ClinVar as [Benign]. Clinvar id is 143438.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154030614-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1250C>T	p.Pro417Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1214C>T	p.Pro405Leu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1250C>T	p.Pro417Leu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1214C>T	p.Pro405Leu	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*586C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*586C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0000368 AC: 4 AN: 108679 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 30981

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000978

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000577

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 12 AN: 177443 Hom.: 0 AF XY: 0.0000309 AC XY: 2 AN XY: 64817

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 43 AN: 1094528 Hom.: 0 Cov.: 33 AF XY: 0.0000470 AC XY: 17 AN XY: 361416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000392

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000368 AC: 4 AN: 108679 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 30981

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000978

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000577

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Benign

Submissions summary: Uncertain:6 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2018	A variant of uncertain significance has been identified in the MECP2 gene. The P405L variant has been reported previously as a de novo variant in the hemizygous state in an individual with cognitive impairment, ADHD, and stereotypic hand movements (Campos et al., 2009). The P405L variant has also been reported previously in the hemizygous state in an individual with cognitive impairment, epilepsy, autism, and stereotypic hand movements; whose mother and sister with borderline intelligence were found to be heterozyous for the variant (Moog et al., 2006). The P405L variant is observed in 8/27147 (0.03%) alleles from individuals of Latino background, including 2 unrelated hemizygous individuals in large population cohorts (Lek et al., 2016). The P405L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -

Rett syndrome Uncertain:1 Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 22, 2021	The allele frequency of the p.Pro405Leu (NM_004992.3) variant in MECP2 is 0.029% in Latino sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro405Leu variant is observed in at least 2 unaffected individuals (GeneDx internal database)(BS2). In summary, the p.Pro405Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2015	c.1214C>T (p.Pro405Leu) is a missense mutation that occurs at a conserved position, and 4/4 in silico tools predict a damaging outcome. Pro405 is a highly conserved amino acid in the carboxy terminal domain, which affects the binding of MECP2 to DNA. However, functional studies have not been carried out to determine the functional impact of this change. The variant has been observed in 1 hemizygous male control from the ExAC cohort, suggesting this variant could be low penetrance, benign, or a mild mutation. The variant has also been cited in at least 2 male intellectually disabled patients (1 de novo occurrence with no family history of ID and 1 maternally inherited with borderline intelligence on both sides of the family). Taken together, the c.1214C>T variant in MECP2 is classified as a variant of uncertain significance (VUS) until additional functional or co-segregation studies are available. -
Benign, 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 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 3.0 (BA1). -

Severe neonatal-onset encephalopathy with microcephaly Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	May 04, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2023	- -

X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 10, 2010

- -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.22
MVP		0.97
ClinPred		0.18	T
GERP RS		5.6
Varity_R		0.53
gMVP		0.40

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: rs61753016; hg19: chrX-153296065;