X-154030655-AGGTGGAGGTGGGGGCAGGGGT-AGGT

Position:

chrX-154030655-AGGTGGAGGTGGGGGCAGGGGT-AGGT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4BP6_Very_StrongBS2

The NM_001110792.2(MECP2):c.1191_1208delCCTGCCCCCACCTCCACC(p.Leu398_Pro403del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000254 in 748,978 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 0 hem., cov: 0)

Exomes 𝑓: 0.000025 ( 0 hom. 5 hem. )

Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 5.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001110792.2.

BP6

Variant X-154030655-AGGTGGAGGTGGGGGCAGG-A is Benign according to our data. Variant chrX-154030655-AGGTGGAGGTGGGGGCAGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 143358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2 linkuse as main transcript	c.1191_1208delCCTGCCCCCACCTCCACC	p.Leu398_Pro403del	disruptive_inframe_deletion	3/3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 linkuse as main transcript	c.1155_1172delCCTGCCCCCACCTCCACC	p.Leu386_Pro391del	disruptive_inframe_deletion	4/4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MECP2	ENST00000453960.7 linkuse as main transcript	c.1191_1208delCCTGCCCCCACCTCCACC	p.Leu398_Pro403del	disruptive_inframe_deletion	3/3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 linkuse as main transcript	c.1155_1172delCCTGCCCCCACCTCCACC	p.Leu386_Pro391del	disruptive_inframe_deletion	4/4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000407218 linkuse as main transcript	c.527_544delCCTGCCCCCACCTCCACC		3_prime_UTR_variant	4/4	5		ENSP00000384865.2	B5MCB4
MECP2	ENST00000628176 linkuse as main transcript	c.527_544delCCTGCCCCCACCTCCACC		3_prime_UTR_variant	5/5	3		ENSP00000486978.1	A0A0D9SFX7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

45532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

10470

FAILED QC

Gnomad AFR

AF:

0.0000909

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:

0.0000401

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000600

AC:

AN:

166750

Hom.:

AF XY:

0.00

AC XY:

AN XY:

60332

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000254

AC:

AN:

748978

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

224762

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000261

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000303

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000439

AC:

AN:

45532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

10470

show subpopulations

Gnomad4 AFR

AF:

0.0000909

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000401

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rett syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

May 03, 2024

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 likely benign. At least the following criteria are met: This variant is present in 21 indivisuals in gnomAD v4 including 5 hemizygotes. The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

- -

not provided

Other:1

not provided, no classification provided

literature only

RettBASE

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over