rs61752981

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP5BS2

This summary comes from the ClinGen Evidence Repository: The p.Pro381Ser variant in MECP2 (NM_004992.4) is observed in at least 19 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro381Ser variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Pro381Ser variant in MECP2 in gnomAD v4.1 is 0.00003574 in the African/African American population (not sufficient to meet BS1 criteria). In summary, the p.Pro381Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10558497/MONDO:0010726/036

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000020 ( 0 hom. 5 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:2

Conservation

PhyloP100: 2.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP5

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1177C>T	p.Pro393Ser	missense_variant	3/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.1141C>T	p.Pro381Ser	missense_variant	4/4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1177C>T	p.Pro393Ser	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1141C>T	p.Pro381Ser	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000407218 linkuse as main transcript	c.*513C>T		3_prime_UTR_variant	4/4	5		ENSP00000384865.2	B5MCB4
MECP2	ENST00000628176 linkuse as main transcript	c.*513C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978.1	A0A0D9SFX7

Frequencies

GnomAD3 genomes

AF:

0.0000369

AC:

AN:

108526

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

30870

show subpopulations

Gnomad AFR

AF:

0.0000337

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:

0.0000577

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000577

AC:

AN:

173418

Hom.:

AF XY:

0.00

AC XY:

AN XY:

62310

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:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1091856

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

359010

show subpopulations

Gnomad4 AFR exome

AF:

0.0000381

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:

0.0000263

Gnomad4 NFE exome

AF:

0.0000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000369

AC:

AN:

108526

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

30870

show subpopulations

Gnomad4 AFR

AF:

0.0000337

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:

0.0000577

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 18, 2024	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 likely benign. At least the following criteria are met: The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -
Likely benign, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 30, 2024	The p.Pro381Ser variant in MECP2 (NM_004992.4) is observed in at least 19 unaffected individuals (internal database - GeneDx, internal database - Invitae) (BS2). The p.Pro381Ser variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). The highest population minor allele frequency of the p.Pro381Ser variant in MECP2 in gnomAD v4.1 is 0.00003574 in the African/African American population (not sufficient to meet BS1 criteria). In summary, the p.Pro381Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2, BP5). -

Severe neonatal-onset encephalopathy with microcephaly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 381 of the MECP2 protein (p.Pro381Ser). This variant is present in population databases (rs61752981, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with MECP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 431897). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MECP2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2016

The P381S variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. A different missense substitution at the same position (P381L) has been reported in association with Rett syndrome; however, the reported individual also harbored two other variants in MECP2, including a known pathogenic variant (Fendri-Kriaa et al., 2012). Other missense variants in nearby residues (P376R; A378G; P388L/S/T) have been reported in the Human Gene Mutation Database in association with MECP2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The P381S variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This 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. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the P381S 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. -

MECP2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The MECP2 c.1141C>T variant is predicted to result in the amino acid substitution p.Pro381Ser. To our knowledge, this variant has not been reported in the literature. A different substitution affecting the same amino acid (p.Pro381Leu) has been reported in an individual with Rett syndrome; however, this individual also has two other MECP2 variants including a frameshift variant (Fendri-Kriaa et al 2012. PubMed ID: 22561697). This variant is reported in 0.0013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.00097

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.26

DEOGEN2

Benign

0.23

T;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.0

N;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.65

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.10

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.32

B;P

Vest4

0.19

MutPred

0.27

Gain of phosphorylation at P381 (P = 0.0062);.;

MVP

0.62

ClinPred

0.11

GERP RS

3.8

Varity_R

0.047

gMVP

0.38

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