rs782171742

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The p.Pro362Ser variant in MECP2 (NM_004992.3) is present in 1 XX and 1 XY individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). The p.Pro362Ser variant in MECP2 is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro362Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA415168068/MONDO:0010726/036

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.000017 ( 0 hom. 7 hem. )

Consequence

MECP2
ENST00000453960.7 missense

Scores

1
9
7

Clinical Significance

Likely benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 4.86
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 Likely_benign. Variant got -4 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MECP2NM_001110792.2 linkuse as main transcriptc.1120C>T p.Pro374Ser missense_variant 3/3 ENST00000453960.7 NP_001104262.1
MECP2NM_004992.4 linkuse as main transcriptc.1084C>T p.Pro362Ser 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.1120C>T p.Pro374Ser missense_variant 3/31 NM_001110792.2 ENSP00000395535 P51608-2
MECP2ENST00000303391.11 linkuse as main transcriptc.1084C>T p.Pro362Ser missense_variant 4/41 NM_004992.4 ENSP00000301948 P1P51608-1
MECP2ENST00000407218.5 linkuse as main transcriptc.*456C>T 3_prime_UTR_variant 4/45 ENSP00000384865
MECP2ENST00000628176.2 linkuse as main transcriptc.*456C>T 3_prime_UTR_variant 5/53 ENSP00000486978

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.0000111
AC:
2
AN:
180544
Hom.:
0
AF XY:
0.0000151
AC XY:
1
AN XY:
66320
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:
0.0000249
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000173
AC:
19
AN:
1097399
Hom.:
0
Cov.:
35
AF XY:
0.0000193
AC XY:
7
AN XY:
362895
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.0000226
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
Bravo
AF:
0.00000756
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 27, 2017A variant of uncertain significance has been identified in the MECP2 gene. The P362S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P362S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P362S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 08, 2023- -
Rett syndrome Benign:1
Likely benign, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelOct 13, 2023The p.Pro362Ser variant in MECP2 (NM_004992.3) is present in 1 XX and 1 XY individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). The p.Pro362Ser variant in MECP2 is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro362Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). -
Intellectual disability Benign:1
Likely benign, criteria provided, single submitterclinical testingDiagnostic Laboratory, Strasbourg University HospitalApr 20, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Uncertain
0.075
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
T;.
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Benign
0.26
T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Benign
1.4
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
0.020
N;N
REVEL
Uncertain
0.40
Sift
Uncertain
0.018
D;D
Sift4G
Benign
0.23
T;T
Polyphen
0.73
P;P
Vest4
0.12
MutPred
0.26
Gain of phosphorylation at P362 (P = 0.0047);.;
MVP
0.59
ClinPred
0.27
T
GERP RS
5.1
Varity_R
0.11
gMVP
0.60

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: rs782171742; hg19: chrX-153296195; COSMIC: COSV57652398; COSMIC: COSV57652398; API