rs587783128

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001110792.2(MECP2):c.-27_-26delAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 964,958 control chromosomes in the GnomAD database, including 2 homozygotes. There are 209 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., 14 hem., cov: 21)

Exomes 𝑓: 0.00071 ( 2 hom. 195 hem. )

Consequence

MECP2
NM_001110792.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 3.23

Publications

1 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 -16 ACMG points.

BP6

Variant X-154097690-CCT-C is Benign according to our data. Variant chrX-154097690-CCT-C is described in ClinVar as Benign. ClinVar VariationId is 156656.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000519 (56/107976) while in subpopulation NFE AF = 0.000973 (50/51369). AF 95% confidence interval is 0.000758. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 56 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.-27_-26delAG		5_prime_UTR_variant	Exon 1 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.-187_-186delAG		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.-27_-26delAG		5_prime_UTR_variant	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.-187_-186delAG		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

107976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000199

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000973

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000249

AC:

AN:

44218

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000461

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000708

AC:

607

AN:

856982

Hom.:

AF XY:

0.000765

AC XY:

195

AN XY:

254886

show subpopulations

African (AFR)

AF:

0.000108

AC:

AN:

18449

American (AMR)

AF:

0.00

AC:

AN:

11959

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10614

East Asian (EAS)

AF:

0.00

AC:

AN:

20713

South Asian (SAS)

AF:

0.00

AC:

AN:

22161

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2827

European-Non Finnish (NFE)

AF:

0.000816

AC:

586

AN:

718248

Other (OTH)

AF:

0.000562

AC:

AN:

33811

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000519

AC:

AN:

107976

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

AN XY:

31232

show subpopulations

African (AFR)

AF:

0.000199

AC:

AN:

30158

American (AMR)

AF:

0.00

AC:

AN:

10405

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2602

East Asian (EAS)

AF:

0.00

AC:

AN:

3356

South Asian (SAS)

AF:

0.00

AC:

AN:

2614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

228

European-Non Finnish (NFE)

AF:

0.000973

AC:

AN:

51369

Other (OTH)

AF:

0.00

AC:

AN:

1471

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00114

Hom.:

Bravo

AF:

0.000427

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 08, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 17, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MECP2 c.-187_-186delAG is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 44218 control chromosomes (gnomAD). The observed variant frequency is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.-187_-186delAG in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Rett syndrome

Benign:2

Feb 18, 2022

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The allele frequency of the c.-187_-186del variant in MECP2 (NM_004992.3) is 0.058% in European (non-Finnish) sub population and 0.033% in African/African-American 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 c.-187_-186del variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). -

Aug 14, 2023

Centre for Population Genomics, CPG

Significance: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 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). -

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Nov 01, 2007

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Nov 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=300/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over