rs797045692

Positions:

• chrX-154030591-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BP5

This summary comes from the ClinGen Evidence Repository: The p.Cys413Arg variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_Supporting). The p.Cys413Arg variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary the p.Cys413Arg variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA208666/MONDO:0010726/032

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 2.50

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1273T>C	p.Cys425Arg	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1237T>C	p.Cys413Arg	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1273T>C	p.Cys425Arg	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1237T>C	p.Cys413Arg	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*609T>C		3_prime_UTR_variant	5/5	3		ENSP00000486978.1
MECP2	ENST00000407218.5	c.*609T>C		downstream_gene_variant		5		ENSP00000384865.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000183 AC: 2 AN: 1095672 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 361838

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: 0.0000217

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Rett syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

May 05, 2023

The p.Cys413Arg variant in MECP2 (NM_004992.3) is absent from gnomAD (PM2_Supporting). The p.Cys413Arg variant in MECP2 (NM_004992.3) is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary the p.Cys413Arg variant in MECP2 (NM_004992.3) is classified as a variant of unknown significance based on the ACMG/AMP criteria (PM2_Supporting, BP5). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.29	T;.
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.45	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.38	T;T
Polyphen		0.0	B;B
Vest4		0.15
MutPred		0.20		Gain of MoRF binding (P = 0.017);.;
MVP		1.0
ClinPred		0.24	T
GERP RS		4.3
Varity_R		0.83
gMVP		0.21

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: rs797045692; hg19: chrX-153296042;