chrX-154097661-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_001110792.2(MECP2):​c.5C>T​(p.Ala2Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002183775: Experimental studies have shown that this missense change affects MECP2 function (PMID:28973632)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Uncertain significance. The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.71
• Publications: 17 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, 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

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002183775: Experimental studies have shown that this missense change affects MECP2 function (PMID: 28973632).; SCV005370062: Published functional studies demonstrate a damaging effect, including impaired methionine excision and increased proteasomal degradation rate (PMID: 28973632)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant X-154097661-G-A is Pathogenic according to our data. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.-156C>T		5_prime_UTR	Exon 1 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-603C>T		5_prime_UTR	Exon 1 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-156C>T		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000631210.1	TSL:1	n.305+7120C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000167 AC: 1 AN: 59894 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000481

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 911162 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 283614

African (AFR) AF: 0.00 AC: 0 AN: 19640

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12528

East Asian (EAS) AF: 0.00 AC: 0 AN: 22395

South Asian (SAS) AF: 0.00 AC: 0 AN: 30233

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21223

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 749902

Other (OTH) AF: 0.00 AC: 0 AN: 36577

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Rett syndrome (4)
1	-	-	not provided (1)
1	-	-	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.55	T
PhyloP100		3.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.070	T
Polyphen		0.0010	B
Vest4		0.48
MutPred		0.31		Loss of helix (P = 0.0167)
MVP		0.88
ClinPred		0.93	D
GERP RS		2.4
PromoterAI		-0.59	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.76
Mutation Taster		=34/66	disease causing (ClinVar)

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;