rs267608460

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001110792.2(MECP2):c.413+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 765,658 control chromosomes in the GnomAD database, including 7 homozygotes. There are 585 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., 90 hem., cov: 24)

Exomes 𝑓: 0.0028 ( 7 hom. 495 hem. )

Consequence

MECP2
NM_001110792.2 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: -2.49

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant X-154032112-C-T is Benign according to our data. Variant chrX-154032112-C-T is described in ClinVar as Benign. ClinVar VariationId is 156060.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00213 (240/112633) while in subpopulation AMR AF = 0.00336 (36/10711). AF 95% confidence interval is 0.00249. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High AC in GnomAd4 at 240 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.413+95G>A		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4 link	c.377+95G>A		intron_variant	Intron 3 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7 link	c.413+95G>A		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11 link	c.377+95G>A		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

240

AN:

112578

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00337

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00246

Gnomad OTH

AF:

0.00131

GnomAD4 exome

AF:

0.00278

AC:

1814

AN:

653025

Hom.:

AF XY:

0.00264

AC XY:

495

AN XY:

187831

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

17806

American (AMR)

AF:

0.00112

AC:

AN:

32020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16117

East Asian (EAS)

AF:

0.00

AC:

AN:

27541

South Asian (SAS)

AF:

0.0000463

AC:

AN:

43241

European-Finnish (FIN)

AF:

0.0110

AC:

408

AN:

37183

Middle Eastern (MID)

AF:

0.000420

AC:

AN:

2383

European-Non Finnish (NFE)

AF:

0.00284

AC:

1265

AN:

445464

Other (OTH)

AF:

0.00301

AC:

AN:

31270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00213

AC:

240

AN:

112633

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

AN XY:

34791

show subpopulations

African (AFR)

AF:

0.000515

AC:

AN:

31051

American (AMR)

AF:

0.00336

AC:

AN:

10711

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3569

South Asian (SAS)

AF:

0.00

AC:

AN:

2767

European-Finnish (FIN)

AF:

0.00885

AC:

AN:

6215

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00246

AC:

131

AN:

53217

Other (OTH)

AF:

0.00130

AC:

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00205

Hom.:

Bravo

AF:

0.00159

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 15, 2003

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Rett syndrome

Benign:1

Oct 12, 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). -

not provided

Other:1

RettBASE

Significance:not provided

Review Status:flagged submission

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.040

(source)

DANN

Benign

0.59

PhyloP100

-2.5

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over