rs111302745

chrX-154030674-G-AchrX-154030674-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Moderate BP6_Moderate

The NM_001110792.2(MECP2):c.1190C>T(p.Pro397Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict 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. P397S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.43

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 -2 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 10 uncertain in NM_001110792.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.25909144).
• BP6: Variant X-154030674-G-A is Benign according to our data. Variant chrX-154030674-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2846315.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1190C>T	p.Pro397Leu	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1154C>T	p.Pro385Leu	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1190C>T	p.Pro397Leu	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1154C>T	p.Pro385Leu	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*526C>T		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*526C>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.17e-7 AC: 1 AN: 1090664 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 358166

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: 0.0000268

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	0.0035	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Benign	0.51
DEOGEN2	Benign	0.33	T;.
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.78	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.58	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.32		Loss of glycosylation at P385 (P = 0.0074);.;
MVP		0.80
ClinPred		0.075	T
GERP RS		0.95
Varity_R		0.065
gMVP		0.33

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: rs111302745; hg19: chrX-153296125;