rs61751446

Positions:

• chrX-154030886-G-A

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.978C>T​(p.Ile326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,210,814 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 146 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 0.00036 (0 hom., 14 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (0 hom. 132 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.216

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 (BayesDel_addAF=-0.498445).
• BP6: Variant X-154030886-G-A is Benign according to our data. Variant chrX-154030886-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154030886-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.216 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000355 (40/112566) while in subpopulation EAS AF= 0.0014 (5/3578). AF 95% confidence interval is 0.000574. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.978C>T	p.Ile326=	synonymous_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.942C>T	p.Ile314=	synonymous_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.978C>T	p.Ile326=	synonymous_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.942C>T	p.Ile314=	synonymous_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 40 AN: 112515 Hom.: 0 Cov.: 23 AF XY: 0.000404 AC XY: 14 AN XY: 34663

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.000362

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000398 AC: 73 AN: 183500 Hom.: 0 AF XY: 0.000397 AC XY: 27 AN XY: 67934

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.000866

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000342 AC: 376 AN: 1098248 Hom.: 0 Cov.: 35 AF XY: 0.000363 AC XY: 132 AN XY: 363602

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.000332

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.000289

Gnomad4 OTH exome AF: 0.000607

GnomAD4 genome AF: 0.000355 AC: 40 AN: 112566 Hom.: 0 Cov.: 23 AF XY: 0.000403 AC XY: 14 AN XY: 34724

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00102

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00140

Gnomad4 SAS AF: 0.000364

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000244

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	curation	RettBASE	Mar 29, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 22, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	MECP2: BP4, BP7 -

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 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). -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2022

- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2017

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.3
DANN	Benign	0.83
FATHMM_MKL	Benign	0.13	N
MutationTaster	Benign	1.0	D;D
Vest4		0.73
GERP RS		-2.1

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: rs61751446; hg19: chrX-153296337; COSMIC: COSV57657340; COSMIC: COSV57657340;