rs61753982

chrX-154031466-GA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):c.414-17del variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00563 in 1,209,376 control chromosomes in the GnomAD database, including 19 homozygotes. There are 2,150 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., 145 hem., cov: 22)
  • Exomes 𝑓: 0.0058 (16 hom. 2005 hem.)
• Consequence: MECP2 NM_001110792.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-154031466-GA-G is Benign according to our data. Variant chrX-154031466-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 156063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031466-GA-G is described in Lovd as [Likely_benign]. Variant chrX-154031466-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00438 (492/112275) while in subpopulation NFE AF= 0.0066 (351/53189). AF 95% confidence interval is 0.00603. There are 3 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.414-17del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.378-17del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.378-17del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.414-17del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 492 AN: 112221 Hom.: 3 Cov.: 22 AF XY: 0.00422 AC XY: 145 AN XY: 34377

Gnomad AFR AF: 0.000745

Gnomad AMI AF: 0.00293

Gnomad AMR AF: 0.00377

Gnomad ASJ AF: 0.00679

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00767

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00663

GnomAD3 exomes AF: 0.00432 AC: 782 AN: 181154 Hom.: 5 AF XY: 0.00408 AC XY: 274 AN XY: 67132

Gnomad AFR exome AF: 0.000614

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00522

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.00601

GnomAD4 exome AF: 0.00576 AC: 6319 AN: 1097101 Hom.: 16 Cov.: 33 AF XY: 0.00553 AC XY: 2005 AN XY: 362565

Gnomad4 AFR exome AF: 0.000417

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00609

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00647

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.00438 AC: 492 AN: 112275 Hom.: 3 Cov.: 22 AF XY: 0.00421 AC XY: 145 AN XY: 34441

Gnomad4 AFR AF: 0.000743

Gnomad4 AMR AF: 0.00376

Gnomad4 ASJ AF: 0.00679

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00767

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.00654

Alfa AF: 0.00523 Hom.: 43

Bravo AF: 0.00430

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5 Other:1

Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 23, 2016	- -
not provided, flagged submission	literature only	RettBASE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2015	- -
Benign, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Rett syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jun 01, 2018	- -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 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). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs61753982; hg19: chrX-153296917;