chrX-154030996-C-T

Position:

• chrX-154030996-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001110792.2(MECP2):​c.868G>A​(p.Ala290Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,098,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2510745).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.868G>A	p.Ala290Thr	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.832G>A	p.Ala278Thr	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.868G>A	p.Ala290Thr	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.832G>A	p.Ala278Thr	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000275 AC: 5 AN: 182147 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098187 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 2 AN XY: 363561

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Benign:2

Likely 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 Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as likely benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). The variant is observed in at least 1 individual with no features of Rett Syndrome (BS2_Supporting, PMID 23696494). The variant has been observed in trans with a MECP2 pathogenic variant (BP2, PMID 23696494) -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 09, 2015	- -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Feb 05, 2014

- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D;D;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N;N;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;D;.
Sift4G	Benign	0.53	T;T;T
Polyphen		0.94	P;D;.
Vest4		0.18
MutPred		0.33		Gain of glycosylation at A278 (P = 0.0163);.;.;
MVP		0.98
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.21
gMVP		0.88

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: rs782086416; hg19: chrX-153296447;