rs61753964

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001110792.2(MECP2):c.1251C>T(p.Pro417=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 1,203,270 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000083 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000082 ( 0 hom. 28 hem. )

Consequence

MECP2
NM_001110792.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.734

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028828979).

BP6

Variant X-154030613-G-A is Benign according to our data. Variant chrX-154030613-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030613-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.734 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1251C>T	p.Pro417=	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.1215C>T	p.Pro405=	synonymous_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1251C>T	p.Pro417=	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1215C>T	p.Pro405=	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000407218.5 linkuse as main transcript	c.*587C>T		3_prime_UTR_variant	4/4	5		ENSP00000384865
MECP2	ENST00000628176.2 linkuse as main transcript	c.*587C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978

Frequencies

GnomAD3 genomes

AF:

0.0000828

AC:

AN:

108696

Hom.:

Cov.:

AF XY:

0.0000968

AC XY:

AN XY:

30990

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:

0.000573

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000135

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

177436

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

64810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000868

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000756

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.0000822

AC:

AN:

1094526

Hom.:

Cov.:

AF XY:

0.0000775

AC XY:

AN XY:

361410

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000430

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.0000269

Gnomad4 NFE exome

AF:

0.0000772

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000828

AC:

AN:

108744

Hom.:

Cov.:

AF XY:

0.0000966

AC XY:

AN XY:

31048

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000575

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000135

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Feb 03, 2006

- -

Rett syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Aug 14, 2023

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 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). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2017

This 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.5

DANN

Benign

0.65

DEOGEN2

Benign

0.099

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.36

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.83

MutationTaster

Benign

1.0

D;D

GERP RS

3.2

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