rs61754444

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.281A>G(p.Lys94Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,210,556 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K94K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.0000082 ( 0 hom. 3 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.49

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

chromosome Xq28 duplication syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
Rett syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
severe neonatal-onset encephalopathy with microcephaly
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
syndromic X-linked intellectual disability Lubs type
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability-psychosis-macroorchidism syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28793418).

BP6

Variant X-154032339-T-C is Benign according to our data. Variant chrX-154032339-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 9 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.281A>G	p.Lys94Arg	missense_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.245A>G	p.Lys82Arg	missense_variant	Exon 3 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.281A>G	p.Lys94Arg	missense_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.245A>G	p.Lys82Arg	missense_variant	Exon 3 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

112874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000927

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183054

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097682

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26390

American (AMR)

AF:

0.00

AC:

AN:

35182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30192

South Asian (SAS)

AF:

0.00

AC:

AN:

54116

European-Finnish (FIN)

AF:

0.0000494

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

841719

Other (OTH)

AF:

0.0000434

AC:

AN:

46067

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000266

AC:

AN:

112874

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

35042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31138

American (AMR)

AF:

0.0000927

AC:

AN:

10782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00

AC:

AN:

2785

European-Finnish (FIN)

AF:

0.000160

AC:

AN:

6240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53244

Other (OTH)

AF:

0.00

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Apr 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 01, 2007

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Rett syndrome

Benign:1

Aug 14, 2023

Centre for Population Genomics, CPG

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

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 Likely benign. At least the following criteria are met: The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting). -

not provided

Benign:1

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.;T;T;T;T;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.29

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

0.90

L;.;.;.;.;.;.

PhyloP100

4.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

N;N;.;.;.;.;.

REVEL

Uncertain

0.44

Sift

Benign

0.046

D;D;.;.;.;.;.

Sift4G

Benign

0.079

T;T;D;T;.;T;D

Polyphen

0.041

B;B;.;.;.;.;.

Vest4

0.31

MutPred

0.17

Loss of ubiquitination at K82 (P = 0.0283);.;Loss of ubiquitination at K82 (P = 0.0283);.;Loss of ubiquitination at K82 (P = 0.0283);.;.;

MVP

0.98

ClinPred

0.14

GERP RS

5.9

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.58

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over