rs61750236

Positions:

• chrX-154030757-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001110792.2(MECP2):​c.1107C>T​(p.Ser369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,209,024 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.00029 (0 hom. 99 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.484

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-154030757-G-A is Benign according to our data. Variant chrX-154030757-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030757-G-A is described in Lovd as [Pathogenic]. Variant chrX-154030757-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.484 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 99 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1107C>T	p.Ser369=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1071C>T	p.Ser357=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1107C>T	p.Ser369=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1071C>T	p.Ser357=	synonymous_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*443C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*443C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0000719 AC: 8 AN: 111289 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33473

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000756

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.000187 AC: 34 AN: 181569 Hom.: 0 AF XY: 0.000209 AC XY: 14 AN XY: 66871

Gnomad AFR exome AF: 0.000157

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000578

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000292 AC: 320 AN: 1097683 Hom.: 0 Cov.: 35 AF XY: 0.000273 AC XY: 99 AN XY: 363119

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.000517

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000320

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000629 AC: 7 AN: 111341 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33535

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000943

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.0000757

Gnomad4 OTH AF: 0.000659

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000102

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2015	- -
Benign, no assertion criteria provided	curation	RettBASE	Feb 04, 2003	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -

Rett syndrome Benign:1

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 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). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2018

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

MECP2: BP4, BP7, BS2 -

MECP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

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	-0.80
CADD	Benign	1.9
DANN	Benign	0.63

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: rs61750236; hg19: chrX-153296208;