rs111302745

Variant names:

• chrX-154030674-G-A
• rs111302745
• NM_001110792.2:c.1190C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030674-G-A
• chrX-154030674-G-C
• chrX-154030674-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 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. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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
• Publications: 1 publications found

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]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 22 benign, 17 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 2846315.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1190C>T	p.Pro397Leu	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1154C>T	p.Pro385Leu	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1190C>T	p.Pro397Leu	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1154C>T	p.Pro385Leu	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

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

African (AFR) AF: 0.00 AC: 0 AN: 26295

American (AMR) AF: 0.00 AC: 0 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19316

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.00 AC: 0 AN: 53993

European-Finnish (FIN) AF: 0.0000268 AC: 1 AN: 37330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3637

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838953

Other (OTH) AF: 0.00 AC: 0 AN: 45835

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

Jul 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;.
PhyloP100		2.4
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs111302745; hg19: chrX-153296125;