rs587783128

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000453960.7(MECP2):​c.-27_-26del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 964,958 control chromosomes in the GnomAD database, including 2 homozygotes. There are 209 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., 14 hem., cov: 21)
Exomes 𝑓: 0.00071 ( 2 hom. 195 hem. )

Consequence

MECP2
ENST00000453960.7 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 3.23
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant X-154097690-CCT-C is Benign according to our data. Variant chrX-154097690-CCT-C is described in ClinVar as [Benign]. Clinvar id is 156656.Status of the report is reviewed_by_expert_panel, 3 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000519 (56/107976) while in subpopulation NFE AF= 0.000973 (50/51369). AF 95% confidence interval is 0.000758. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.-27_-26del 5_prime_UTR_variant 1/3 ENST00000453960.7 NP_001104262.1
MECP2NM_004992.4 linkuse as main transcriptc.-187_-186del 5_prime_UTR_variant 1/4 ENST00000303391.11 NP_004983.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MECP2ENST00000303391.11 linkuse as main transcriptc.-187_-186del 5_prime_UTR_variant 1/41 NM_004992.4 ENSP00000301948 P1P51608-1
MECP2ENST00000453960.7 linkuse as main transcriptc.-27_-26del 5_prime_UTR_variant 1/31 NM_001110792.2 ENSP00000395535 P51608-2

Frequencies

GnomAD3 genomes
AF:
0.000519
AC:
56
AN:
107976
Hom.:
0
Cov.:
21
AF XY:
0.000448
AC XY:
14
AN XY:
31232
show subpopulations
Gnomad AFR
AF:
0.000199
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000973
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000249
AC:
11
AN:
44218
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
9828
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000461
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000708
AC:
607
AN:
856982
Hom.:
2
AF XY:
0.000765
AC XY:
195
AN XY:
254886
show subpopulations
Gnomad4 AFR exome
AF:
0.000108
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000816
Gnomad4 OTH exome
AF:
0.000562
GnomAD4 genome
AF:
0.000519
AC:
56
AN:
107976
Hom.:
0
Cov.:
21
AF XY:
0.000448
AC XY:
14
AN XY:
31232
show subpopulations
Gnomad4 AFR
AF:
0.000199
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000973
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00114
Hom.:
5
Bravo
AF:
0.000427

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 08, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 02, 2017This 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. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 17, 2019Variant summary: MECP2 c.-187_-186delAG is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 44218 control chromosomes (gnomAD). The observed variant frequency is approximately 30 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. To our knowledge, no occurrence of c.-187_-186delAG in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has 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 benign. -
Rett syndrome Benign:2
Benign, criteria provided, single submittercurationCentre for Population Genomics, CPGAug 14, 2023This 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 panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelFeb 18, 2022The allele frequency of the c.-187_-186del variant in MECP2 (NM_004992.3) is 0.058% in European (non-Finnish) sub population and 0.033% in African/African-American 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). In summary, the c.-187_-186del variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). -
X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1
Uncertain significance, no assertion criteria providedcurationRettBASENov 01, 2007- -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587783128; hg19: chrX-153363147; API