rs201314910

Positions:

• chrX-154030695-G-A
• chrX-154030695-G-C
• chrX-154030695-G-T

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.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170175/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (0 hom. 37 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:8
• Conservation: PhyloP100: 2.85

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.1169C>T	p.Ala390Val	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1133C>T	p.Ala378Val	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1169C>T	p.Ala390Val	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1133C>T	p.Ala378Val	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*505C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*505C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 11 AN: 109524 Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1 AN XY: 31794

Gnomad AFR AF: 0.0000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000966

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000287

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000153

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000515 AC: 9 AN: 174908 Hom.: 0 AF XY: 0.0000319 AC XY: 2 AN XY: 62720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.000146

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000515

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000129 AC: 141 AN: 1093137 Hom.: 0 Cov.: 35 AF XY: 0.000103 AC XY: 37 AN XY: 359747

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.0000518

Gnomad4 EAS exome AF: 0.000796

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.0000654

GnomAD4 genome AF: 0.000100 AC: 11 AN: 109524 Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1 AN XY: 31794

Gnomad4 AFR AF: 0.0000333

Gnomad4 AMR AF: 0.0000966

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000287

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000153

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ExAC AF: 0.0000743 AC: 9

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	curation	RettBASE	Mar 10, 2010	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2019	Variant summary: MECP2 c.1133C>T (p.Ala378Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 175188 control chromosomes (2 hemizygotes). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. c.1133C>T has been reported in the literature in one female individual affected with Rett Syndrome and patient's unaffected father (Fukuda_2005). This report suggests the variant does not associate with Rett Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2014	- -

not provided Pathogenic:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2021	This variant is associated with the following publications: (PMID: 15737703) -

Rett syndrome Benign:2

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). -
Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	May 10, 2022	The allele frequency of the p.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2023

- -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 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	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.22	T;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.53	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.050	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.11	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.90	P;P
Vest4		0.11
MutPred		0.35		Gain of methylation at K377 (P = 0.0497);.;
MVP		0.82
ClinPred		0.067	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.42

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: rs201314910; hg19: chrX-153296146;