X-154092209-T-C

Variant names:

• chrX-154092209-T-C
• rs786205892
• NM_004992.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_004992.4(MECP2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,084,268 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MECP2 NM_004992.4 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• 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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 5 codons. Genomic position: 154092197. Lost 0.009 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_004992.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 4	ENST00000303391.11	NP_004983.1
MECP2	NM_001110792.2	c.62+5395A>G		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.1A>G	p.Met1?	start_lost	Exon 2 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000453960.7	c.62+5395A>G		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084268 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 352692

African (AFR) AF: 0.00 AC: 0 AN: 26017

American (AMR) AF: 0.00 AC: 0 AN: 34832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18937

East Asian (EAS) AF: 0.00 AC: 0 AN: 29412

South Asian (SAS) AF: 0.00 AC: 0 AN: 53872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832356

Other (OTH) AF: 0.00 AC: 0 AN: 45280

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T;T;T;T;.
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.0	.;.;.;.;.
PhyloP100		3.4
PROVEAN	Benign	-0.65	N;.;.;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.
Vest4		0.76
ClinPred		0.48	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
Mutation Taster		=43/157	disease causing

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: rs786205892; hg19: chrX-153357667;