rs267608332

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_001110792.2(MECP2):c.1196_1202delCCCCACC(p.Pro399LeufsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 552,051 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000061 ( 0 hom., 0 hem., cov: 0)

Exomes 𝑓: 0.000039 ( 0 hom. 4 hem. )

Consequence

MECP2
NM_001110792.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.20

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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, 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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 137 pathogenic variants in the truncated region.

PP5

Variant X-154030661-AGGTGGGG-A is Pathogenic according to our data. Variant chrX-154030661-AGGTGGGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 143384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 21 XL,Unknown,AD gene.

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	UniProt
MECP2	NM_001110792.2	MANE Select	c.1196_1202delCCCCACC	p.Pro399LeufsTer20	frameshift	Exon 3 of 3	NP_001104262.1	A0A140VKC4
MECP2	NM_004992.4	MANE Plus Clinical	c.1160_1166delCCCCACC	p.Pro387LeufsTer20	frameshift	Exon 4 of 4	NP_004983.1	D3YJ43
MECP2	NM_001316337.2		c.881_887delCCCCACC	p.Pro294LeufsTer20	frameshift	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1196_1202delCCCCACC	p.Pro399LeufsTer20	frameshift	Exon 3 of 3	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1160_1166delCCCCACC	p.Pro387LeufsTer20	frameshift	Exon 4 of 4	ENSP00000301948.6	P51608-1
MECP2	ENST00000630151.3	TSL:5	c.1160_1166delCCCCACC	p.Pro387LeufsTer20	frameshift	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes

AF:

0.0000609

AC:

AN:

16414

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000115

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000755

AC:

AN:

132529

AF XY:

0.0000204

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:

0.0000155

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000392

AC:

AN:

535637

Hom.:

AF XY:

0.0000255

AC XY:

AN XY:

156659

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13489

American (AMR)

AF:

0.00

AC:

AN:

17484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7694

East Asian (EAS)

AF:

0.00

AC:

AN:

7836

South Asian (SAS)

AF:

0.00

AC:

AN:

22278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13189

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1775

European-Non Finnish (NFE)

AF:

0.0000462

AC:

AN:

432938

Other (OTH)

AF:

0.0000528

AC:

AN:

18954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.590

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:

0.0000609

AC:

AN:

16414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

4652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3899

American (AMR)

AF:

0.00

AC:

AN:

1398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

448

East Asian (EAS)

AF:

0.00

AC:

AN:

763

South Asian (SAS)

AF:

0.00

AC:

AN:

374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

509

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000115

AC:

AN:

8681

Other (OTH)

AF:

0.00

AC:

AN:

209

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Rett syndrome (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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