chrX-154030648-C-T

Variant names:

• chrX-154030648-C-T
• rs63094662
• NM_001110792.2:c.1216G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP5 BS2 BA1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Glu394Lys variant in MECP2 is 0.035% in East Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Glu394Lys variant is observed in at least 2 unaffected individuals (internal database) (BS2). Computational analysis prediction tools suggest that the p.Glu394Lys variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Glu394Lys variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Glu394Lys variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170197/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 1 hem., cov: 16)
  • Exomes 𝑓: 0.00011 (0 hom. 27 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 1.61
• Publications: 11 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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1216G>A	p.Glu406Lys	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1180G>A	p.Glu394Lys	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.901G>A	p.Glu301Lys	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.1216G>A	p.Glu406Lys	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1180G>A	p.Glu394Lys	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1180G>A	p.Glu394Lys	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000829 AC: 6 AN: 72333 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.0000558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000455

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000101

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000874 AC: 15 AN: 171619 AF XY: 0.0000801

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000749

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000297

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000778

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 88 AN: 803418 Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 27 AN XY: 243984

African (AFR) AF: 0.00 AC: 0 AN: 19306

American (AMR) AF: 0.000102 AC: 3 AN: 29311

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11852

East Asian (EAS) AF: 0.00126 AC: 17 AN: 13492

South Asian (SAS) AF: 0.000116 AC: 5 AN: 43263

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18666

Middle Eastern (MID) AF: 0.000389 AC: 1 AN: 2572

European-Non Finnish (NFE) AF: 0.0000866 AC: 55 AN: 634914

Other (OTH) AF: 0.000233 AC: 7 AN: 30042

GnomAD4 genome AF: 0.0000829 AC: 6 AN: 72333 Hom.: 0 Cov.: 16 AF XY: 0.0000624 AC XY: 1 AN XY: 16021

African (AFR) AF: 0.0000558 AC: 1 AN: 17925

American (AMR) AF: 0.00 AC: 0 AN: 5609

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1974

East Asian (EAS) AF: 0.000455 AC: 1 AN: 2197

South Asian (SAS) AF: 0.00 AC: 0 AN: 1144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 144

European-Non Finnish (NFE) AF: 0.000101 AC: 4 AN: 39647

Other (OTH) AF: 0.00 AC: 0 AN: 901

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.000263 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Rett syndrome (3)
-	-	1	MECP2-related disorder (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.47
Sift	Benign	0.046	D
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.89
ClinPred		0.017	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.21
Mutation Taster		=93/7	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: rs63094662; hg19: chrX-153296099;