X-154031179-G-A

Position:

• chrX-154031179-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_001110792.2(MECP2):​c.685C>T​(p.Pro229Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000637 in 1,098,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 4 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.58

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MECP2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.33232749).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.685C>T	p.Pro229Ser	missense_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.649C>T	p.Pro217Ser	missense_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.685C>T	p.Pro229Ser	missense_variant	3/3	1	NM_001110792.2	ENSP00000395535
MECP2	ENST00000303391.11	c.649C>T	p.Pro217Ser	missense_variant	4/4	1	NM_004992.4	ENSP00000301948	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000637 AC: 7 AN: 1098262 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 4 AN XY: 363616

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000712

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

MECP2: PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.11	T;T;.;.
Sift4G	Uncertain	0.058	T;T;.;T
Polyphen		0.26	B;B;.;.
Vest4		0.11
MutPred		0.31		Gain of phosphorylation at P217 (P = 0.0458);.;Gain of phosphorylation at P217 (P = 0.0458);.;
MVP		0.89
ClinPred		0.64	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.71

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: rs786205894; hg19: chrX-153296630; COSMIC: COSV57657270; COSMIC: COSV57657270;