rs782239416

chrX-154030987-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1 BP4_Moderate BP6_Very_Strong BS2

The NM_001110792.2(MECP2):c.877G>A(p.Ala293Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000537 in 1,210,009 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A293G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000056 (0 hom. 19 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:6
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 9 uncertain in NM_001110792.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.22918028).
• BP6: Variant X-154030987-C-T is Benign according to our data. Variant chrX-154030987-C-T is described in ClinVar as [Benign]. Clinvar id is 386725.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Hemizygotes in GnomAdExome at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.877G>A	p.Ala293Thr	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.841G>A	p.Ala281Thr	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.877G>A	p.Ala293Thr	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.841G>A	p.Ala281Thr	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 111988 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34170

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000937 AC: 17 AN: 181466 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67216

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000556 AC: 61 AN: 1098021 Hom.: 0 Cov.: 35 AF XY: 0.0000523 AC XY: 19 AN XY: 363447

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 111988 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34170

Gnomad4 AFR AF: 0.0000975

Gnomad4 AMR AF: 0.0000934

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 28, 2018	Variant summary: MECP2 c.841G>A (p.Ala281Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 176575 control chromosomes, including 7 hemizygotes (gnomAD). The observed variant frequency is approximately 11.5 folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.841G>A in individuals affected with Rett Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign and uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	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. -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2022

- -

Rett syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Oct 13, 2023

The allele frequency of the p.Ala281Thr variant in MECP2 (NM_004992.3) is 0.037% in the South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ala281Thr variant is observed in at least 8 unaffected individuals (internal database - Invitae) (BS2). In summary, the p.Ala281Thr variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

MECP2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Uncertain	0.51	D;.;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	0.97	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.91	N;N;.
REVEL	Uncertain	0.44
Sift	Benign	0.11	T;T;.
Sift4G	Benign	0.56	T;T;D
Polyphen		0.92	P;P;.
Vest4		0.13
MutPred		0.23		Gain of phosphorylation at A281 (P = 0.0408);.;.;
MVP		0.99
ClinPred		0.021	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
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: rs782239416; hg19: chrX-153296438; COSMIC: COSV57658195; COSMIC: COSV57658195;