rs61748423

chrX-154030931-G-AchrX-154030931-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001110792.2(MECP2):c.933C>T(p.Thr311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,210,623 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,171 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., 58 hem., cov: 23)
  • Exomes 𝑓: 0.0031 (4 hom. 1113 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.609

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008170664).
• BP6: Variant X-154030931-G-A is Benign according to our data. Variant chrX-154030931-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030931-G-A is described in Lovd as [Likely_benign]. Variant chrX-154030931-G-A is described in Lovd as [Benign]. Variant chrX-154030931-G-A is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-0.609 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00203 (228/112391) while in subpopulation NFE AF= 0.00292 (155/53129). AF 95% confidence interval is 0.00254. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 58 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.933C>T	p.Thr311=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.897C>T	p.Thr299=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.933C>T	p.Thr311=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.897C>T	p.Thr299=	synonymous_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.00203 AC: 228 AN: 112339 Hom.: 1 Cov.: 23 AF XY: 0.00168 AC XY: 58 AN XY: 34497

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.0630

Gnomad AMR AF: 0.000747

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000560

Gnomad SAS AF: 0.000727

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.00180 AC: 330 AN: 183486 Hom.: 1 AF XY: 0.00166 AC XY: 113 AN XY: 67930

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000911

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.000505

Gnomad SAS exome AF: 0.000681

Gnomad FIN exome AF: 0.000437

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.00307 AC: 3376 AN: 1098232 Hom.: 4 Cov.: 35 AF XY: 0.00306 AC XY: 1113 AN XY: 363590

Gnomad4 AFR exome AF: 0.000985

Gnomad4 AMR exome AF: 0.000937

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.000563

Gnomad4 SAS exome AF: 0.000739

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00203 AC: 228 AN: 112391 Hom.: 1 Cov.: 23 AF XY: 0.00168 AC XY: 58 AN XY: 34559

Gnomad4 AFR AF: 0.000484

Gnomad4 AMR AF: 0.000746

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000562

Gnomad4 SAS AF: 0.000729

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.00292

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00107 Hom.: 7

Bravo AF: 0.00254

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00381 AC: 11

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00357 AC: 24

ExAC AF: 0.00178 AC: 216

EpiCase AF: 0.00453

EpiControl AF: 0.00338

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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 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	Dec 05, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Rett syndrome Benign:1

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 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). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 17, 2021

- -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2016

Other strong data supporting benign classification;Synonymous alterations with insufficient evidence to classify as benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.9
Dann	Benign	0.75
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0082	T
MutationTaster	Benign	1.0	D;D
Sift4G	Uncertain	0.053	T
Vest4		0.39
MVP		0.77
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61748423; hg19: chrX-153296382; COSMIC: COSV104409427; COSMIC: COSV104409427;