X-154030594-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001110792.2(MECP2):​c.1270G>A​(p.Val424Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,204,116 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 125 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 4 hem., cov: 22)
Exomes 𝑓: 0.00021 ( 0 hom. 121 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

2
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.363
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0071368515).
BP6
Variant X-154030594-C-T is Benign according to our data. Variant chrX-154030594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 143446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030594-C-T is described in Lovd as [Likely_benign]. Variant chrX-154030594-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000147 (16/108707) while in subpopulation SAS AF= 0.00249 (6/2407). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.1270G>A p.Val424Ile missense_variant 3/3 ENST00000453960.7 NP_001104262.1
MECP2NM_004992.4 linkuse as main transcriptc.1234G>A p.Val412Ile missense_variant 4/4 ENST00000303391.11 NP_004983.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkuse as main transcriptc.1270G>A p.Val424Ile missense_variant 3/31 NM_001110792.2 ENSP00000395535 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.1234G>A p.Val412Ile missense_variant 4/41 NM_004992.4 ENSP00000301948 P1P51608-1
MECP2ENST00000628176.2 linkuse as main transcriptc.*606G>A 3_prime_UTR_variant 5/53 ENSP00000486978
MECP2ENST00000407218.5 linkuse as main transcript downstream_gene_variant 5 ENSP00000384865

Frequencies

GnomAD3 genomes
AF:
0.000147
AC:
16
AN:
108662
Hom.:
0
Cov.:
22
AF XY:
0.000129
AC XY:
4
AN XY:
31064
show subpopulations
Gnomad AFR
AF:
0.0000671
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000983
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000289
Gnomad SAS
AF:
0.00248
Gnomad FIN
AF:
0.000176
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000958
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000449
AC:
81
AN:
180258
Hom.:
0
AF XY:
0.000684
AC XY:
45
AN XY:
65744
show subpopulations
Gnomad AFR exome
AF:
0.0000767
Gnomad AMR exome
AF:
0.000109
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000722
Gnomad SAS exome
AF:
0.00341
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000112
Gnomad OTH exome
AF:
0.000444
GnomAD4 exome
AF:
0.000214
AC:
234
AN:
1095409
Hom.:
0
Cov.:
32
AF XY:
0.000335
AC XY:
121
AN XY:
361687
show subpopulations
Gnomad4 AFR exome
AF:
0.0000758
Gnomad4 AMR exome
AF:
0.0000852
Gnomad4 ASJ exome
AF:
0.0000517
Gnomad4 EAS exome
AF:
0.000530
Gnomad4 SAS exome
AF:
0.00249
Gnomad4 FIN exome
AF:
0.000104
Gnomad4 NFE exome
AF:
0.0000760
Gnomad4 OTH exome
AF:
0.000174
GnomAD4 genome
AF:
0.000147
AC:
16
AN:
108707
Hom.:
0
Cov.:
22
AF XY:
0.000129
AC XY:
4
AN XY:
31119
show subpopulations
Gnomad4 AFR
AF:
0.0000670
Gnomad4 AMR
AF:
0.0000981
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000290
Gnomad4 SAS
AF:
0.00249
Gnomad4 FIN
AF:
0.000176
Gnomad4 NFE
AF:
0.0000958
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000109
Hom.:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000297
AC:
2
ExAC
AF:
0.000494
AC:
60
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 07, 2017- -
Benign, no assertion criteria providedcurationRettBASEDec 05, 2013- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 16, 2016- -
not provided Benign:3
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 25, 2021This variant is associated with the following publications: (PMID: 12872250, 11055898, 24715477, 23810759) -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Rett syndrome Benign:1
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). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 17, 2017This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
3.3
DANN
Benign
0.93
DEOGEN2
Benign
0.30
T;.
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.76
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.0071
T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.20
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.10
N;N
REVEL
Uncertain
0.39
Sift
Benign
0.59
T;T
Sift4G
Benign
0.26
T;T
Polyphen
0.0
B;B
Vest4
0.020
MVP
0.92
ClinPred
0.011
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.033
gMVP
0.11

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: rs61753966; hg19: chrX-153296045; COSMIC: COSV57655267; COSMIC: COSV57655267; API