rs267608636

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.1474C>T(p.Pro492Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,209,666 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P492L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.61

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23509154).

BP6

Variant X-154030390-G-A is Benign according to our data. Variant chrX-154030390-G-A is described in ClinVar as [Benign]. Clinvar id is 143477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030390-G-A is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1474C>T	p.Pro492Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.1438C>T	p.Pro480Ser	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.1474C>T	p.Pro492Ser	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1438C>T	p.Pro480Ser	missense_variant	4/4	1	NM_004992.4	P1	P51608-1
MECP2	ENST00000628176.2 linkuse as main transcript	c.*810C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111378

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33546

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000387

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183504

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

67934

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:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098236

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363592

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:

0.00000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111430

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33608

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000388

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 14, 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 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 3.0 (BA1). -

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

May 14, 2010

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.16

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

-0.045

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.23

T;T

Polyphen

0.27

B;B

Vest4

0.24

MutPred

0.068

Gain of phosphorylation at P480 (P = 0.0031);.;

MVP

1.0

ClinPred

0.22

GERP RS

5.8

Varity_R

0.20

gMVP

0.19

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