X-154097661-G-T

Variant names:

• chrX-154097661-G-T
• rs179363901
• NM_001110792.2:c.5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001110792.2(MECP2):​c.5C>A​(p.Ala2Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 911,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. A2V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000022 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154097661-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.-156C>A		5_prime_UTR	Exon 1 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.-603C>A		5_prime_UTR	Exon 1 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.5C>A	p.Ala2Asp	missense	Exon 1 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-156C>A		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6
	MECP2	ENST00000631210.1	TSL:1	n.305+7120C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000219 AC: 2 AN: 911185 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 283635

⚠️ 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: 19641

American (AMR) AF: 0.00 AC: 0 AN: 15512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12529

East Asian (EAS) AF: 0.00 AC: 0 AN: 22396

South Asian (SAS) AF: 0.00 AC: 0 AN: 30237

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3152

European-Non Finnish (NFE) AF: 0.00000267 AC: 2 AN: 749916

Other (OTH) AF: 0.00 AC: 0 AN: 36578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.51	T
PhyloP100		3.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		0.86	P
Vest4		0.52
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.82
ClinPred		0.98	D
GERP RS		2.4
PromoterAI		-0.56	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.86
Mutation Taster		=59/41	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: rs179363901; hg19: chrX-153363118; COSMIC: COSV57656924; COSMIC: COSV57656924;