rs797045691

Positions:

chrX-154030633-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro399Ser variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro399Ser variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Pro399Ser variant in MECP2 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA206184/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 0.000015 ( 0 hom. 2 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:2

Conservation

PhyloP100: 2.54

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]

MECP2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1231C>T	p.Pro411Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.1195C>T	p.Pro399Ser	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1231C>T	p.Pro411Ser	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1195C>T	p.Pro399Ser	missense_variant	4/4	1	NM_004992.4	P1	P51608-1
MECP2	ENST00000407218.5 linkuse as main transcript	c.*567C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2 linkuse as main transcript	c.*567C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000370

AC:

AN:

107981

Hom.:

Cov.:

AF XY:

0.0000329

AC XY:

AN XY:

30351

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000983

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:

0.0000580

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000171

AC:

AN:

175912

Hom.:

AF XY:

0.0000311

AC XY:

AN XY:

64370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

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:

0.0000254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1093362

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

360762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000178

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000370

AC:

AN:

107981

Hom.:

Cov.:

AF XY:

0.0000329

AC XY:

AN XY:

30351

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000983

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000580

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2018

The p.P399S variant (also known as c.1195C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 1195. The proline at codon 399 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 14, 2023

- -

Rett syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Dec 09, 2022

The allele frequency of the p.Pro399Ser variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro399Ser variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Pro399Ser variant in MECP2 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.22

T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.097

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

-0.90

N;.

MutationTaster

Benign

0.71

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.2

N;N

REVEL

Benign

0.26

Sift

Benign

0.45

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.0010

B;B

Vest4

0.057

MutPred

0.27

Gain of phosphorylation at P399 (P = 7e-04);.;

MVP

0.88

ClinPred

0.048

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.21

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over