chrX-154030994-G-A

Variant names:

• chrX-154030994-G-A
• rs61750248
• NM_001110792.2:c.870C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001110792.2(MECP2):​c.870C>T​(p.Ala290Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,210,218 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 158 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 0.00044 (0 hom., 11 hem., cov: 24)
  • Exomes 𝑓: 0.00035 (0 hom. 147 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.36

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-154030994-G-A is Benign according to our data. Variant chrX-154030994-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030994-G-A is described in Lovd as [Likely_benign]. Variant chrX-154030994-G-A is described in Lovd as [Benign]. Variant chrX-154030994-G-A is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000437 (49/112104) while in subpopulation EAS AF = 0.00254 (9/3543). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position FAILED quality control check.
• BS2: High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.870C>T	p.Ala290Ala	synonymous_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.834C>T	p.Ala278Ala	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.870C>T	p.Ala290Ala	synonymous_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.834C>T	p.Ala278Ala	synonymous_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.000437 AC: 49 AN: 112050 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000936

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000301

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000489 AC: 89 AN: 181911 AF XY: 0.000549

Gnomad AFR exome AF: 0.000876

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000352 AC: 386 AN: 1098114 Hom.: 0 Cov.: 35 AF XY: 0.000404 AC XY: 147 AN XY: 363514

Gnomad4 AFR exome AF: 0.000341 AC: 9 AN: 26401

Gnomad4 AMR exome AF: 0.000398 AC: 14 AN: 35204

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19386

Gnomad4 EAS exome AF: 0.00281 AC: 85 AN: 30206

Gnomad4 SAS exome AF: 0.000185 AC: 10 AN: 54147

Gnomad4 FIN exome AF: 0.000149 AC: 6 AN: 40402

Gnomad4 NFE exome AF: 0.000284 AC: 239 AN: 842140

Gnomad4 Remaining exome AF: 0.000456 AC: 21 AN: 46093

GnomAD4 genome AF: 0.000437 AC: 49 AN: 112104 Hom.: 0 Cov.: 24 AF XY: 0.000321 AC XY: 11 AN XY: 34282

Gnomad4 AFR AF: 0.000648 AC: 0.000647564 AN: 0.000647564

Gnomad4 AMR AF: 0.0000935 AC: 0.0000934929 AN: 0.0000934929

Gnomad4 ASJ AF: 0.000378 AC: 0.000377501 AN: 0.000377501

Gnomad4 EAS AF: 0.00254 AC: 0.00254022 AN: 0.00254022

Gnomad4 SAS AF: 0.000369 AC: 0.00036914 AN: 0.00036914

Gnomad4 FIN AF: 0.000164 AC: 0.000163773 AN: 0.000163773

Gnomad4 NFE AF: 0.000301 AC: 0.000301392 AN: 0.000301392

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000347 Hom.: 2

Bravo AF: 0.000412

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Oct 11, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MECP2 c.834C>T (p.Ala278Ala) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 49/85676 (18 hemizygotes, 1/1748), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic MECP2 variant of 1/120481. In addition, multiple publications and a reputable database has cited the variant as "benign/silent polymorphism." Therefore, the variant of interest has been classified as Benign. -

Mar 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

not specified Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 10, 2010

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Rett syndrome Benign:1

Mar 13, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 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 3.0 (BA1). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 14, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 07, 2021

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	-0.90
CADD	Benign	0.0080
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=98/2	polymorphism

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: rs61750248; hg19: chrX-153296445; COSMIC: COSV57657600; COSMIC: COSV57657600;