rs63586860

Positions:

Variant summary

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

The ENST00000453960.7(MECP2):c.1242C>T(p.Pro414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,202,989 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 115 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 0.00019 ( 0 hom., 5 hem., cov: 21)

Exomes 𝑓: 0.00027 ( 0 hom. 110 hem. )

Consequence

MECP2
ENST00000453960.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.79

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=0.03350517).

BP6

Variant X-154030622-G-A is Benign according to our data. Variant chrX-154030622-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030622-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.79 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1242C>T	p.Pro414=	synonymous_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 linkuse as main transcript	c.1206C>T	p.Pro402=	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.1242C>T	p.Pro414=	synonymous_variant	3/3	1	NM_001110792.2	ENSP00000395535		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1206C>T	p.Pro402=	synonymous_variant	4/4	1	NM_004992.4	ENSP00000301948	P1	P51608-1
MECP2	ENST00000407218.5 linkuse as main transcript	c.*578C>T		3_prime_UTR_variant	4/4	5		ENSP00000384865
MECP2	ENST00000628176.2 linkuse as main transcript	c.*578C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978

Frequencies

GnomAD3 genomes

AF:

0.000193

AC:

AN:

108815

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

31133

show subpopulations

Gnomad AFR

AF:

0.0000336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000976

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000407

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000327

Gnomad OTH

AF:

0.000688

GnomAD3 exomes

AF:

0.000232

AC:

AN:

176812

Hom.:

AF XY:

0.000248

AC XY:

AN XY:

64592

show subpopulations

Gnomad AFR exome

AF:

0.0000805

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000145

Gnomad SAS exome

AF:

0.000683

Gnomad FIN exome

AF:

0.0000753

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000268

AC:

293

AN:

1094126

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

110

AN XY:

361230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.0000270

Gnomad4 NFE exome

AF:

0.000280

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000193

AC:

AN:

108863

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

AN XY:

31191

show subpopulations

Gnomad4 AFR

AF:

0.0000335

Gnomad4 AMR

AF:

0.0000975

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000408

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000327

Gnomad4 OTH

AF:

0.000679

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000256

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MECP2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	- -

not specified

Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Dec 05, 2013

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Rett syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 13, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.6

DANN

Benign

0.66

DEOGEN2

Benign

0.060

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.36

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

D;D

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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