rs61748414

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6

The NM_001110792.2(MECP2):c.515C>G(p.Thr172Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,210,358 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T172N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 9.45

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001110792.2

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant X-154031349-G-C is Benign according to our data. Variant chrX-154031349-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143593.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.515C>G	p.Thr172Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4 linkuse as main transcript	c.479C>G	p.Thr160Ser	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.515C>G	p.Thr172Ser	missense_variant	3/3	1	NM_001110792.2		P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.479C>G	p.Thr160Ser	missense_variant	4/4	1	NM_004992.4	P1	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112141

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34291

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000940

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182854

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67518

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098217

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363571

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:

0.00000356

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112141

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34291

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000940

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rett syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 21, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in a male patient with autistic disorder [PMID 21600714] -
Likely benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 10, 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 pathogenic. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). -

Autism, susceptibility to, X-linked 3

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

May 18, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.35

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;.;D;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.64

D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.69

N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.1

N;N;.;.;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.021

D;D;.;.;.

Sift4G

Benign

0.16

T;T;.;T;D

Polyphen

0.73

P;P;.;.;.

Vest4

0.52

MutPred

0.38

Gain of glycosylation at T160 (P = 0.0694);.;Gain of glycosylation at T160 (P = 0.0694);.;.;

MVP

1.0

ClinPred

0.46

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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