rs781816931

Variant names:

• chrX-154030640-G-A
• rs781816931
• NM_001110792.2:c.1224C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ser396= variant in MECP2 (NM_004992.3) is 0.15% in European (Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ser396= variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Ser396= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA207604/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 9 hem., cov: 20)
  • Exomes 𝑓: 0.00027 (0 hom. 100 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 0.490

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 -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1224C>T	p.Ser408Ser	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1188C>T	p.Ser396Ser	synonymous_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1224C>T	p.Ser408Ser	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1188C>T	p.Ser396Ser	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 21 AN: 107298 Hom.: 0 Cov.: 20 AF XY: 0.000303 AC XY: 9 AN XY: 29736

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000233

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000281 AC: 49 AN: 174480 Hom.: 0 AF XY: 0.000328 AC XY: 21 AN XY: 64016

Gnomad AFR exome AF: 0.0000845

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000728

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 294 AN: 1092401 Hom.: 0 Cov.: 33 AF XY: 0.000278 AC XY: 100 AN XY: 360117

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.000275

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.000196 AC: 21 AN: 107298 Hom.: 0 Cov.: 20 AF XY: 0.000303 AC XY: 9 AN XY: 29736

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00121

Gnomad4 NFE AF: 0.000233

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 2

Bravo AF: 0.000170

ExAC AF: 0.000363 AC: 44

EpiCase AF: 0.000273

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:1

Jan 22, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MECP2: BP4, BP7, BS2 -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome Benign:1

Dec 09, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the p.Ser396= variant in MECP2 (NM_004992.3) is 0.15% in European (Finnish) sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ser396= variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Ser396= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2_supporting). -

Inborn genetic diseases Benign:1

Aug 25, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Aug 29, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.85
DANN	Benign	0.65
DEOGEN2	Benign	0.070	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.86	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs781816931; hg19: chrX-153296091; COSMIC: COSV100318075; COSMIC: COSV100318075;