rs61753975

chrX-154030498-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):c.1366G>A(p.Ala456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,209,785 control chromosomes in the GnomAD database, including 1 homozygotes. There are 324 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A456V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., 17 hem., cov: 22)
  • Exomes 𝑓: 0.00085 (1 hom. 307 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.556

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014973402).
• BP6: Variant X-154030498-C-T is Benign according to our data. Variant chrX-154030498-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030498-C-T is described in Lovd as [Likely_benign]. Variant chrX-154030498-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000771 (86/111598) while in subpopulation NFE AF= 0.00117 (62/53021). AF 95% confidence interval is 0.000936. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1366G>A	p.Ala456Thr	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1330G>A	p.Ala444Thr	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1366G>A	p.Ala456Thr	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1330G>A	p.Ala444Thr	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000628176.2	c.*702G>A		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 85 AN: 111547 Hom.: 0 Cov.: 22 AF XY: 0.000504 AC XY: 17 AN XY: 33719

Gnomad AFR AF: 0.000359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000474

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000828

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.000949 AC: 174 AN: 183388 Hom.: 1 AF XY: 0.000958 AC XY: 65 AN XY: 67826

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000729

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.000751

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000849 AC: 932 AN: 1098187 Hom.: 1 Cov.: 32 AF XY: 0.000844 AC XY: 307 AN XY: 363557

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.000351

Gnomad4 FIN exome AF: 0.000815

Gnomad4 NFE exome AF: 0.000939

Gnomad4 OTH exome AF: 0.000564

GnomAD4 genome AF: 0.000771 AC: 86 AN: 111598 Hom.: 0 Cov.: 22 AF XY: 0.000503 AC XY: 17 AN XY: 33780

Gnomad4 AFR AF: 0.000358

Gnomad4 AMR AF: 0.000568

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000828

Gnomad4 NFE AF: 0.00117

Gnomad4 OTH AF: 0.000657

Alfa AF: 0.00122 Hom.: 24

Bravo AF: 0.000790

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.000988 AC: 120

EpiCase AF: 0.00142

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2018	Variant summary: MECP2 c.1330G>A (p.Ala444Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 200146 control chromosomes in the gnomAD database, including 55 hemizygotes. The observed variant frequency is approximately 118.11 fold above 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 experimental evidence demonstrating the impact on protein function of c.1330G>A have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2013	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. -
Benign, no assertion criteria provided	curation	RettBASE	May 14, 2010	- -

Rett syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID: 11738860, PMID: 11055898). This variant did not segregate in a similarly affected family member (BS4_Supporting, PMID: 11738860) -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	14
Dann	Benign	0.89
DEOGEN2	Benign	0.24	T;.
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.040	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.79	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0050	B;B
Vest4		0.098
MVP		0.94
ClinPred		0.0026	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.042
gMVP		0.39

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: rs61753975; hg19: chrX-153295949; COSMIC: COSV57653878; COSMIC: COSV57653878;