rs61753965

Positions:

• chrX-154030612-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.1252C>T​(p.Gln418Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000914 in 1,094,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.39

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 Pathogenic. Variant got 14 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. Fraction of 0.164 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154030612-G-A is Pathogenic according to our data. Variant chrX-154030612-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 143441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030612-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1252C>T	p.Gln418Ter	stop_gained	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1216C>T	p.Gln406Ter	stop_gained	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1252C>T	p.Gln418Ter	stop_gained	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.1216C>T	p.Gln406Ter	stop_gained	4/4	1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000407218.5	c.*588C>T		3_prime_UTR_variant	4/4	5		ENSP00000384865
MECP2	ENST00000628176.2	c.*588C>T		3_prime_UTR_variant	5/5	3		ENSP00000486978

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094534 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361380

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	curation	RettBASE	Sep 27, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Jan 18, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 13, 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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4). (PMID: 10986043, 22476991, 14560307, ClinVar Variation ID: 143441) This variant is absent from gnomAD (PM2_Supporting). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Gln437Alafs*49) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143441). This premature translational stop signal has been observed in individuals with MECP2-related conditions (PMID: 10986043, 14560307, 22476991). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln406*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the MECP2 protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2022

Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29655203, 14560307, 22476991, 23452848, 10986043) -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Sep 27, 2012

- -

MECP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The MECP2 c.1216C>T variant is predicted to result in premature protein termination (p.Gln406*). This variant has been reported in a family with two carrier females displaying borderline intelligence and two males with intellectual development disorder (Meloni et al. 2000. PubMed ID: 10986043), a female with psychomotor developmental delay (Kleefstra et al. 2004. PubMed ID: 14560307), as well as individuals with epilepsy and neurodevelopmental disorders (Lindy et al. 2018. PubMed ID: 29655203; Table S4, McKnight et al. 2021. PubMed ID: 34926809). Additionally, this nonsense variant occurs upstream from the distal‐most de novo truncating variant in an affected patient reported to date (McKnight et al. 2021. PubMed ID: 34837432). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.6

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: rs61753965; hg19: chrX-153296063;