rs61748381

Variant names:

• chrX-154031226-G-A
• rs61748381
• NM_001110792.2:c.638C>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.Ala201Val (NM_004992) variant in MECP2 is 1.045% 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). In summary, the p.Ala201Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211932/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 41 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (6 hom. 339 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:19
• Conservation: PhyloP100: 2.69
• Publications: 19 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 -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: 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.638C>T	p.Ala213Val	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.602C>T	p.Ala201Val	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.323C>T	p.Ala108Val	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.638C>T	p.Ala213Val	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.602C>T	p.Ala201Val	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.602C>T	p.Ala201Val	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 181 AN: 111078 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00274

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.000333

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00135

GnomAD2 exomes AF: 0.00143 AC: 262 AN: 183434 AF XY: 0.00130

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000806

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00100 AC: 1103 AN: 1098250 Hom.: 6 Cov.: 34 AF XY: 0.000932 AC XY: 339 AN XY: 363604

African (AFR) AF: 0.00193 AC: 51 AN: 26401

American (AMR) AF: 0.000738 AC: 26 AN: 35207

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

East Asian (EAS) AF: 0.0129 AC: 391 AN: 30206

South Asian (SAS) AF: 0.000979 AC: 53 AN: 54148

European-Finnish (FIN) AF: 0.000247 AC: 10 AN: 40533

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4137

European-Non Finnish (NFE) AF: 0.000617 AC: 520 AN: 842134

Other (OTH) AF: 0.00104 AC: 48 AN: 46098

GnomAD4 genome AF: 0.00163 AC: 181 AN: 111134 Hom.: 0 Cov.: 23 AF XY: 0.00123 AC XY: 41 AN XY: 33372

African (AFR) AF: 0.00125 AC: 38 AN: 30521

American (AMR) AF: 0.00274 AC: 29 AN: 10579

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.0119 AC: 42 AN: 3530

South Asian (SAS) AF: 0.00154 AC: 4 AN: 2598

European-Finnish (FIN) AF: 0.000333 AC: 2 AN: 6006

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

European-Non Finnish (NFE) AF: 0.00121 AC: 64 AN: 52856

Other (OTH) AF: 0.00133 AC: 2 AN: 1506

Alfa AF: 0.00128 Hom.: 49

Bravo AF: 0.00204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.00154 AC: 187

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
1	-	3	Rett syndrome (4)
-	-	3	Severe neonatal-onset encephalopathy with microcephaly (3)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0053	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	-0.35	N
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.44
Sift	Benign	0.11	T
Sift4G	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.051
MVP		1.0
ClinPred		0.0038	T
GERP RS		4.6
Varity_R		0.086
gMVP		0.35
Mutation Taster		=96/4	polymorphism (auto)

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: rs61748381; hg19: chrX-153296677; COSMIC: COSV105147301; COSMIC: COSV105147301;