rs61751445

Positions:

• chrX-154030896-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. BS2 PP3 BP5 BS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Thr311Met variant in MECP2 (NM_004992.3) is 0.022% and 0.01% in "Other" and South Asian 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.Thr311Met variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2) and found in 2 patients with an alternate molecular basis of disease (Baylor Genetics internal database, Invitae internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). As this variant meets 2 strong and 1 supporting benign criteria it can be classified as benign even though in silico predictions meet PP3. In summary, the p.Thr311Met variant in MECP2 is classified as benign for Rett syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170409/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 44 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:10
• Conservation: PhyloP100: 8.99

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 Benign. Variant got -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.968C>T	p.Thr323Met	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.932C>T	p.Thr311Met	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.968C>T	p.Thr323Met	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.932C>T	p.Thr311Met	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112460 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34612

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000381 AC: 7 AN: 183507 Hom.: 0 AF XY: 0.0000294 AC XY: 2 AN XY: 67941

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000116 AC: 127 AN: 1098236 Hom.: 0 Cov.: 35 AF XY: 0.000121 AC XY: 44 AN XY: 363592

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000739

Gnomad4 FIN exome AF: 0.0000987

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112512 Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1 AN XY: 34674

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	This variant is associated with the following publications: (PMID: 22277191, 16672765, 28250423) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2018	- -

Rett syndrome Uncertain:1 Benign:2

Benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Feb 19, 2022	The allele frequency of the p.Thr311Met variant in MECP2 (NM_004992.3) is 0.022% and 0.01% in "Other" and South Asian 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.Thr311Met variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2) and found in 2 patients with an alternate molecular basis of disease (Baylor Genetics internal database, Invitae internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). As this variant meets 2 strong and 1 supporting benign criteria it can be classified as benign even though in silico predictions meet PP3. In summary, the p.Thr311Met variant in MECP2 is classified as benign for Rett syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Sep 27, 2012	- -
Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 09, 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 likely 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). Variant is found in an individual with an alternate molecular basis of disease (BP5). (ClinVar Variation ID:36496) The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2018	Variant summary: MECP2 c.932C>T (p.Thr311Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 178987 control chromosomes including 2 hemizygotes (gnomAD). The observed variant frequency is approximately 4.7 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. The variant, c.932C>T, has been reported in the literature in one individual affected with Rett Syndrome (Kim_2006). These data do not allow any conclusion about variant significance. 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 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Uncertain significance, no assertion criteria provided

curation

RettBASE

Sep 27, 2012

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 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	0.18
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.14	T;D
Polyphen		1.0	D;D
Vest4		0.18
MVP		1.0
ClinPred		0.24	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.91

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: rs61751445; hg19: chrX-153296347; COSMIC: COSV57654149; COSMIC: COSV57654149;