rs61749737

Positions:

• chrX-154031149-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Gln227Glu variant in MECP2 (NM_004992.3) has been reported in an individual with clinical features of MECP2-related conditions (PMID 17383248). The p.Gln227Glu variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Gln227Glu variant is observed in at least 1 unaffected male (internal database - Invitae) (BS2_supporting). In summary, the p.Gln227Glu variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170355/MONDO:0010726/016

• 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:3 B:1
• Conservation: PhyloP100: 3.27

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.
• BS2: 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.715C>G	p.Gln239Glu	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.679C>G	p.Gln227Glu	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.715C>G	p.Gln239Glu	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.679C>G	p.Gln227Glu	missense_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1098238 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 1 AN XY: 363592

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: 0.00000237

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Mar 15, 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 a variant of uncertain significance. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). -
Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Oct 11, 2022	The p.Gln227Glu variant in MECP2 (NM_004992.3) has been reported in an individual with clinical features of MECP2-related conditions (PMID 17383248). The p.Gln227Glu variant in MECP2 is absent from gnomAD (PM2_supporting). The p.Gln227Glu variant is observed in at least 1 unaffected male (internal database - Invitae) (BS2_supporting). In summary, the p.Gln227Glu variant in MECP2 is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (PM2_supporting, BS2_supporting). -

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

Uncertain significance, no assertion criteria provided

curation

RettBASE

Nov 01, 2007

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.34	T;.;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.35	N;N;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.072	T;T;.;.
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.018	B;B;.;.
Vest4		0.25
MutPred		0.24		Gain of ubiquitination at K223 (P = 0.0249);.;Gain of ubiquitination at K223 (P = 0.0249);.;
MVP		1.0
ClinPred		0.26	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.60

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: rs61749737; hg19: chrX-153296600;