rs267608572

Variant names:

• chrX-154030690-C-G
• rs267608572
• NM_001110792.2:c.1174G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154030690-C-G
• chrX-154030690-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001110792.2(MECP2):​c.1174G>C​(p.Val392Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,087,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V392M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330
• Publications: 0 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 2 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 26 benign, 16 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08819708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1174G>C	p.Val392Leu	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1138G>C	p.Val380Leu	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.1174G>C	p.Val392Leu	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1138G>C	p.Val380Leu	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1087368 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 355522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26168

American (AMR) AF: 0.00 AC: 0 AN: 34933

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19151

East Asian (EAS) AF: 0.00 AC: 0 AN: 30059

South Asian (SAS) AF: 0.00 AC: 0 AN: 53274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38165

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3626

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836389

Other (OTH) AF: 0.00 AC: 0 AN: 45603

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.11
DANN	Benign	0.51
DEOGEN2	Benign	0.26	T;.
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		0.33
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.58	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.18	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0010	B;B
Vest4		0.032
MutPred		0.26		Gain of glycosylation at P381 (P = 0.0651);.;
MVP		0.69
ClinPred		0.022	T
GERP RS		1.9
Varity_R		0.058
gMVP		0.22
Mutation Taster		=99/1	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: rs267608572; hg19: chrX-153296141; COSMIC: COSV105147252; COSMIC: COSV105147252;