rs267608341

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.*98dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,148,758 control chromosomes in the GnomAD database, including 9 homozygotes. There are 816 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., 108 hem., cov: 22)

Exomes 𝑓: 0.0023 ( 6 hom. 708 hem. )

Consequence

MECP2
NM_001110792.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.16

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-154030268-G-GT is Benign according to our data. Variant chrX-154030268-G-GT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00391 (437/111695) while in subpopulation AFR AF = 0.00826 (254/30743). AF 95% confidence interval is 0.00743. There are 3 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 437 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.*98dupA		3_prime_UTR_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.*98dupA		3_prime_UTR_variant	Exon 4 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.*98dupA		3_prime_UTR_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.*98dupA		3_prime_UTR_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

438

AN:

111640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00828

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00152

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00833

Gnomad NFE

AF:

0.00202

Gnomad OTH

AF:

0.000666

GnomAD2 exomes

AF:

0.00239

AC:

424

AN:

177362

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.00925

Gnomad AMR exome

AF:

0.00349

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.0000739

Gnomad FIN exome

AF:

0.000135

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00225

AC:

2337

AN:

1037063

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

708

AN XY:

317559

show subpopulations

African (AFR)

AF:

0.00860

AC:

215

AN:

25007

American (AMR)

AF:

0.00403

AC:

139

AN:

34519

Ashkenazi Jewish (ASJ)

AF:

0.00211

AC:

AN:

18916

East Asian (EAS)

AF:

0.0000667

AC:

AN:

29978

South Asian (SAS)

AF:

0.00222

AC:

116

AN:

52273

European-Finnish (FIN)

AF:

0.000128

AC:

AN:

39001

Middle Eastern (MID)

AF:

0.00979

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.00211

AC:

1667

AN:

789391

Other (OTH)

AF:

0.00259

AC:

114

AN:

43996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.00391

AC:

437

AN:

111695

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

108

AN XY:

33883

show subpopulations

African (AFR)

AF:

0.00826

AC:

254

AN:

30743

American (AMR)

AF:

0.00634

AC:

AN:

10568

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3575

South Asian (SAS)

AF:

0.00153

AC:

AN:

2617

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6060

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00202

AC:

107

AN:

53061

Other (OTH)

AF:

0.000658

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00327

Hom.:

Bravo

AF:

0.00499

Asia WGS

AF:

0.00159

AC:

AN:

2522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome

Benign:2

Feb 18, 2024

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 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). -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 05, 2013

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=100/0

polymorphism (auto)

(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