rs782171742

chrX-154030744-G-AchrX-154030744-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_001110792.2(MECP2):c.1120C>T(p.Pro374Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,097,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts 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. P374A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000017 (0 hom. 7 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 4.86

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25782746).
• BP6: Variant X-154030744-G-A is Benign according to our data. Variant chrX-154030744-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 429415.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1120C>T	p.Pro374Ser	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1084C>T	p.Pro362Ser	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1120C>T	p.Pro374Ser	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1084C>T	p.Pro362Ser	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*456C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*456C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 180544 Hom.: 0 AF XY: 0.0000151 AC XY: 1 AN XY: 66320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000249

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1097399 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 7 AN XY: 362895

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000226

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 27, 2017

A variant of uncertain significance has been identified in the MECP2 gene. The P362S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P362S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P362S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

- -

Rett syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Oct 13, 2023

The p.Pro362Ser variant in MECP2 (NM_004992.3) is present in 1 XX and 1 XY individual in gnomAD (0.0011%) (not sufficient to meet BS1 criteria). The p.Pro362Ser variant in MECP2 is observed in at least 3 unaffected individuals (internal database - Invitae) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Pro362Ser variant in MECP2 is classified as Likely Benign based on the ACMG/AMP criteria (BS2). -

Intellectual disability Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.020	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.23	T;T
Polyphen		0.73	P;P
Vest4		0.12
MutPred		0.26		Gain of phosphorylation at P362 (P = 0.0047);.;
MVP		0.59
ClinPred		0.27	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.60

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: rs782171742; hg19: chrX-153296195; COSMIC: COSV57652398; COSMIC: COSV57652398;