X-154031511-G-C

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.414-61C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,166,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., 18 hem., cov: 23)

Exomes 𝑓: 0.00050 ( 0 hom. 169 hem. )

Consequence

MECP2
NM_001110792.2 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.445

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=-0.88).

BP6

Variant X-154031511-G-C is Benign according to our data. Variant chrX-154031511-G-C is described in ClinVar as Benign. ClinVar VariationId is 156070.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000544 (61/112107) while in subpopulation NFE AF = 0.000997 (53/53165). AF 95% confidence interval is 0.000782. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 61 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.414-61C>G		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.378-61C>G		intron_variant	Intron 3 of 3	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.414-61C>G		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2		P51608-2
MECP2	ENST00000303391.11 link	c.378-61C>G		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6		P51608-1

Frequencies

GnomAD3 genomes

AF:

0.000553

AC:

AN:

112054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000283

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000997

Gnomad OTH

AF:

0.00199

GnomAD4 exome

AF:

0.000502

AC:

529

AN:

1054439

Hom.:

AF XY:

0.000519

AC XY:

169

AN XY:

325411

show subpopulations

African (AFR)

AF:

0.0000391

AC:

AN:

25585

American (AMR)

AF:

0.000199

AC:

AN:

35142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19124

East Asian (EAS)

AF:

0.0000333

AC:

AN:

30028

South Asian (SAS)

AF:

0.000698

AC:

AN:

52994

European-Finnish (FIN)

AF:

0.000102

AC:

AN:

39245

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

3212

European-Non Finnish (NFE)

AF:

0.000577

AC:

464

AN:

804433

Other (OTH)

AF:

0.000224

AC:

AN:

44676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000544

AC:

AN:

112107

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

34255

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30862

American (AMR)

AF:

0.000282

AC:

AN:

10629

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2695

European-Finnish (FIN)

AF:

0.000163

AC:

AN:

6122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000997

AC:

AN:

53165

Other (OTH)

AF:

0.00197

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00103

Hom.:

Bravo

AF:

0.000416

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked intellectual disability-psychosis-macroorchidism syndrome

Uncertain:1

Feb 15, 2002

RettBASE

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

- -

Rett syndrome

Benign:1

Mar 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). -

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

-0.88

CADD

Benign

(source)

DANN

Benign

0.60

PhyloP100

0.45

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