X-154030501-C-T

Variant names:

• chrX-154030501-C-T
• rs193922677
• NM_001110792.2:c.1363G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala443Thr variant in MECP2 (NM_004992.3) is 0.015% in Latino population and 0.014% in East Asian population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala443Thr variant is observed in at least 2 unaffected individuals (RettBASE, PMID 22277191, GeneDx internal database, Invitae internal database) (BS2). In summary, the p.Ala443Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199489/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000095 (0 hom. 32 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:8
• Conservation: PhyloP100: 1.40
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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.1363G>A	p.Ala455Thr	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1327G>A	p.Ala443Thr	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.1048G>A	p.Ala350Thr	missense	Exon 5 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.1363G>A	p.Ala455Thr	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1327G>A	p.Ala443Thr	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1327G>A	p.Ala443Thr	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111516 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.000766

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000873 AC: 16 AN: 183347 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.0000855

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000947 AC: 104 AN: 1098183 Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 32 AN XY: 363549

African (AFR) AF: 0.0000379 AC: 1 AN: 26401

American (AMR) AF: 0.000199 AC: 7 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54149

European-Finnish (FIN) AF: 0.0000741 AC: 3 AN: 40477

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.000101 AC: 85 AN: 842125

Other (OTH) AF: 0.0000434 AC: 2 AN: 46097

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111568 Hom.: 0 Cov.: 22 AF XY: 0.000148 AC XY: 5 AN XY: 33760

African (AFR) AF: 0.0000325 AC: 1 AN: 30735

American (AMR) AF: 0.000189 AC: 2 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3539

South Asian (SAS) AF: 0.000768 AC: 2 AN: 2604

European-Finnish (FIN) AF: 0.000165 AC: 1 AN: 6056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53017

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	not specified (2)
-	-	2	Rett syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	MECP2-related disorder (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)
-	1	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.080	N
REVEL	Uncertain	0.38
Sift	Benign	0.85	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.14
MVP		0.89
ClinPred		0.014	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.035
gMVP		0.51
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: rs193922677; hg19: chrX-153295952; COSMIC: COSV100318369; COSMIC: COSV100318369;