rs63390262

Positions:

• chrX-154030668-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro387Leu (NM_004992.3) variant in MECP2 is 0.026% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro387Leu variant is observed in at least 2 unaffected individuals (PMID 12161600, GeneDx internal database) (BS2). In summary, the p.Pro387Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170185/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 3 hem., cov: 20)
  • Exomes 𝑓: 0.000067 (0 hom. 31 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:8
• Conservation: PhyloP100: 2.66

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 -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1196C>T	p.Pro399Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1160C>T	p.Pro387Leu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1196C>T	p.Pro399Leu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1160C>T	p.Pro387Leu	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*532C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*532C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9 AN: 108861 Hom.: 0 Cov.: 20 AF XY: 0.0000964 AC XY: 3 AN XY: 31119 FAILED QC

Gnomad AFR AF: 0.000168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000404

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000577

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000752 AC: 13 AN: 172961 Hom.: 0 AF XY: 0.0000948 AC XY: 6 AN XY: 63267

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000265

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000651

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000671 AC: 73 AN: 1088299 Hom.: 0 Cov.: 36 AF XY: 0.0000870 AC XY: 31 AN XY: 356327

Gnomad4 AFR exome AF: 0.0000762

Gnomad4 AMR exome AF: 0.0000854

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000633

Gnomad4 OTH exome AF: 0.0000437

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000826 AC: 9 AN: 108906 Hom.: 0 Cov.: 20 AF XY: 0.0000962 AC XY: 3 AN XY: 31174

Gnomad4 AFR AF: 0.000167

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000406

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000577

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000491

ExAC AF: 0.0000993 AC: 12

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 13, 2021	The allele frequency of the p.Pro387Leu (NM_004992.3) variant in MECP2 is 0.026% in South Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro387Leu variant is observed in at least 2 unaffected individuals (PMID 12161600, GeneDx internal database) (BS2). In summary, the p.Pro387Leu variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Sep 25, 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 between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2021	This variant is associated with the following publications: (PMID: 11309367, 16708070, 26755454, 28447035, 29206688) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2016

The p.P387L variant (also known as c.1160C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 1160. The proline at codon 387 is replaced by leucine, an amino acid with similar properties. This variant was originally reported in a mentally retarded patient (Couvert P et al. Hum. Mol. Genet., 2001 Apr;10:941-6). In addition, this variant was identified in homozygosity in a female with clinical suspicion of Rett syndrome; however, it was also found in her unaffected father (Bhanushali AA et al. J Clin Neurosci, 2016 Mar;25:127-9). This variant was previously reported in the SNPDatabase as rs63390262. In the NHLBI Exome Sequencing Project (ESP), this variant was not observed in 6325 samples with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

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

Uncertain significance, no assertion criteria provided

curation

RettBASE

Apr 10, 2002

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 30, 2023

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 22, 2017

Variant summary: The MECP2 c.1160C>T (p.Pro387Leu) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 17/186675 control chromosomes (gnomAD) at a frequency of 0.0000911, which is approximately 11 times the estimated maximal expected allele frequency of a pathogenic MECP2 variant (0.0000083), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported via a publication in a homozygous female suspected to have Rett syndrome (Bhanushali_2016), however, her father also carried the variant and was stated to be mentally normal. In addition, one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as likely benign. -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 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	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.43	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.42	B;P
Vest4		0.31
MVP		0.83
ClinPred		0.067	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.44

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: rs63390262; hg19: chrX-153296119;