rs61749739

chrX-154031142-G-AchrX-154031142-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):c.722C>T(p.Ser241Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000329 in 1,208,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 123 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S241S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (0 hom. 115 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.35

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36688653).
• BP6: Variant X-154031142-G-A is Benign according to our data. Variant chrX-154031142-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 143659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031142-G-A is described in Lovd as [Benign]. Variant chrX-154031142-G-A is described in Lovd as [Pathogenic].
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.722C>T	p.Ser241Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.686C>T	p.Ser229Leu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.722C>T	p.Ser241Leu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.686C>T	p.Ser229Leu	missense_variant	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes AF: 0.000173 AC: 19 AN: 109871 Hom.: 0 Cov.: 23 AF XY: 0.000248 AC XY: 8 AN XY: 32207

Gnomad AFR AF: 0.0000999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.000381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000248

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000158 AC: 29 AN: 183449 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67897

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000344 AC: 378 AN: 1098215 Hom.: 0 Cov.: 36 AF XY: 0.000316 AC XY: 115 AN XY: 363571

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.000310

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.0000740

Gnomad4 NFE exome AF: 0.000397

Gnomad4 OTH exome AF: 0.000477

GnomAD4 genome AF: 0.000173 AC: 19 AN: 109871 Hom.: 0 Cov.: 23 AF XY: 0.000248 AC XY: 8 AN XY: 32207

Gnomad4 AFR AF: 0.0000999

Gnomad4 AMR AF: 0.000191

Gnomad4 ASJ AF: 0.000381

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000248

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 4

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	curation	RettBASE	Feb 15, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 13, 2024

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 3.0, 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 3.0 (BA1). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2020

This variant is associated with the following publications: (PMID: 17387578, 12872250, 12111644, 22615490, 17046689, 23912219, 10767337) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;T;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	0.81	D;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Benign	0.079	T;D;.;D
Polyphen		0.81	P;P;.;.
Vest4		0.29
MVP		0.99
ClinPred		0.053	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.40

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: rs61749739; hg19: chrX-153296593;