X-154030666-G-A

Variant names:

• chrX-154030666-G-A
• rs61753000
• NM_001110792.2:c.1198C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Pro388Ser (NM_004992.3) variant in MECP2 is 0.039% in a 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). In summary, the p.Pro388Ser variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274535/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 5 hem., cov: 20)
  • Exomes 𝑓: 0.000051 (0 hom. 15 hem.)
• Consequence: MECP2 ENST00000453960.7 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:9
• Conservation: PhyloP100: 0.964
• Publications: 6 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.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000453960.7. 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.1198C>T	p.Pro400Ser	missense	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1162C>T	p.Pro388Ser	missense	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.883C>T	p.Pro295Ser	missense	Exon 5 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.1198C>T	p.Pro400Ser	missense	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1162C>T	p.Pro388Ser	missense	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1162C>T	p.Pro388Ser	missense	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000826 AC: 9 AN: 108899 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000194

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000405

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000961

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000750 AC: 13 AN: 173258 AF XY: 0.0000631

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.0000732

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000779

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000514 AC: 56 AN: 1089064 Hom.: 0 Cov.: 36 AF XY: 0.0000420 AC XY: 15 AN XY: 357116

African (AFR) AF: 0.0000761 AC: 2 AN: 26264

American (AMR) AF: 0.000114 AC: 4 AN: 35145

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19324

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30153

South Asian (SAS) AF: 0.00 AC: 0 AN: 53959

European-Finnish (FIN) AF: 0.0000272 AC: 1 AN: 36824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3653

European-Non Finnish (NFE) AF: 0.0000513 AC: 43 AN: 837904

Other (OTH) AF: 0.0000436 AC: 2 AN: 45838

GnomAD4 genome AF: 0.0000826 AC: 9 AN: 108899 Hom.: 0 Cov.: 20 AF XY: 0.000160 AC XY: 5 AN XY: 31185

African (AFR) AF: 0.0000335 AC: 1 AN: 29834

American (AMR) AF: 0.000194 AC: 2 AN: 10292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2608

East Asian (EAS) AF: 0.00 AC: 0 AN: 3454

South Asian (SAS) AF: 0.000405 AC: 1 AN: 2469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000961 AC: 5 AN: 52049

Other (OTH) AF: 0.00 AC: 0 AN: 1461

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	Rett syndrome (4)
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	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	0.075
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.96
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.17	N
REVEL	Uncertain	0.49
Sift	Benign	0.36	T
Sift4G	Benign	0.19	T
Polyphen		0.0050	B
Vest4		0.32
MutPred		0.82		Gain of phosphorylation at P388 (P = 9e-04)
MVP		0.97
ClinPred		0.016	T
GERP RS		4.7
Varity_R		0.095
gMVP		0.44
Mutation Taster		=76/24	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: rs61753000; hg19: chrX-153296117; COSMIC: COSV57656772; COSMIC: COSV57656772;