X-154030690-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Val380Met (NM_004992.3) variant in MECP2 is 0.138% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the p.Val380Met variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199319/MONDO:0010726/016

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 6 hem., cov: 21)

Exomes 𝑓: 0.00019 ( 0 hom. 65 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:9

Conservation

PhyloP100: 0.330

Publications

5 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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MECP2	NM_001110792.2	MANE Select	c.1174G>A	p.Val392Met	missense	Exon 3 of 3	NP_001104262.1
MECP2	NM_004992.4	MANE Plus Clinical	c.1138G>A	p.Val380Met	missense	Exon 4 of 4	NP_004983.1
MECP2	NM_001316337.2		c.859G>A	p.Val287Met	missense	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1174G>A	p.Val392Met	missense	Exon 3 of 3	ENSP00000395535.2
MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1138G>A	p.Val380Met	missense	Exon 4 of 4	ENSP00000301948.6
MECP2	ENST00000630151.3	TSL:5	c.1138G>A	p.Val380Met	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

98023

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00109

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:

0.000249

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000348

AC:

AN:

172540

AF XY:

0.000374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000216

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

204

AN:

1087366

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

AN XY:

355520

show subpopulations

African (AFR)

AF:

0.000115

AC:

AN:

26168

American (AMR)

AF:

0.00100

AC:

AN:

34933

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19151

East Asian (EAS)

AF:

0.0000333

AC:

AN:

30059

South Asian (SAS)

AF:

0.000150

AC:

AN:

53273

European-Finnish (FIN)

AF:

0.000105

AC:

AN:

38165

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3626

European-Non Finnish (NFE)

AF:

0.000177

AC:

148

AN:

836388

Other (OTH)

AF:

0.000110

AC:

AN:

45603

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000224

AC:

AN:

98040

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

25534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25888

American (AMR)

AF:

0.00108

AC:

AN:

9220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2425

East Asian (EAS)

AF:

0.00

AC:

AN:

3230

South Asian (SAS)

AF:

0.00

AC:

AN:

2139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4825

Middle Eastern (MID)

AF:

0.00

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.000249

AC:

AN:

48189

Other (OTH)

AF:

0.00

AC:

AN:

1295

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.584

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000304

AC:

ExAC

AF:

0.000273

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Rett syndrome (3)

Inborn genetic diseases (1)

MECP2-related disorder (1)

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (1)

Severe neonatal-onset encephalopathy with microcephaly (1)

X-linked intellectual disability-psychosis-macroorchidism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.29

CADD

Benign

1.3

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.24

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.0

PhyloP100

0.33

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.34

REVEL

Uncertain

0.31

Sift

Benign

0.19

Sift4G

Benign

0.10

Polyphen

0.13

Vest4

0.057

MVP

0.57

ClinPred

0.0083

GERP RS

1.9

Varity_R

0.041

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over