rs2071569

chrX-154031524-G-AchrX-154031524-G-CchrX-154031524-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001110792.2(MECP2):c.414-74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,132,367 control chromosomes in the GnomAD database, including 1,757 homozygotes. There are 6,272 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (133 hom., 694 hem., cov: 23)
  • Exomes 𝑓: 0.018 (1624 hom. 5578 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.111

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.414-74C>T		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.378-74C>T		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.378-74C>T		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.414-74C>T		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2031 AN: 111782 Hom.: 133 Cov.: 23 AF XY: 0.0204 AC XY: 694 AN XY: 33954

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.00344

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0240

GnomAD4 exome AF: 0.0180 AC: 18327 AN: 1020530 Hom.: 1624 AF XY: 0.0185 AC XY: 5578 AN XY: 302320

Gnomad4 AFR exome AF: 0.00148

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.000424

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.00550

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.0175

GnomAD4 genome AF: 0.0181 AC: 2028 AN: 111837 Hom.: 133 Cov.: 23 AF XY: 0.0204 AC XY: 694 AN XY: 34019

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.0761

Gnomad4 ASJ AF: 0.000756

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00344

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00652 Hom.: 47

Bravo AF: 0.0307

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, flagged submission	literature only	RettBASE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Rett syndrome Benign:1

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). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Jun 12, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.076
Dann	Benign	0.49

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: rs2071569; hg19: chrX-153296975; COSMIC: COSV57651739; COSMIC: COSV57651739;