X-154032556-C-G

Variant names:

• chrX-154032556-C-G
• rs61754421
• NM_001110792.2:c.64G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001110792.2(MECP2):​c.64G>C​(p.Glu22Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000922 in 1,084,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 missense, splice_region
• Scores: Splicing: ADA: 0.8999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.83
• Publications: 2 publications found

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]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39929986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.64G>C	p.Glu22Gln	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.28G>C	p.Glu10Gln	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.64G>C	p.Glu22Gln	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.28G>C	p.Glu10Gln	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084804 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 354426

African (AFR) AF: 0.00 AC: 0 AN: 26273

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19356

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 53990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836291

Other (OTH) AF: 0.00 AC: 0 AN: 45834

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Uncertain:2

Mar 21, 2024

Centre for Population Genomics, CPG

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Nov 15, 2007

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T;T;T;T;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;T;D;T;D;D;D;D;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.81	L;.;.;.;.;.;.;.;.
PhyloP100		5.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.86	N;N;.;.;.;.;.;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.010	D;D;.;.;.;.;.;.;.
Sift4G	Benign	0.20	T;D;T;D;.;T;T;.;.
Polyphen		0.99	D;D;.;.;.;.;.;.;.
Vest4		0.75
MutPred		0.081		Gain of methylation at K12 (P = 0.0699);.;Gain of methylation at K12 (P = 0.0699);.;Gain of methylation at K12 (P = 0.0699);.;.;Gain of methylation at K12 (P = 0.0699);Gain of methylation at K12 (P = 0.0699);
MVP		0.98
ClinPred		0.88	D
GERP RS		5.7
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.27
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Pathogenic	0.77
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

Other links and lift over

dbSNP: rs61754421; hg19: chrX-153298007;