rs201314910

Variant names:

• chrX-154030695-G-A
• rs201314910
• NM_001110792.2:c.1169C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030695-G-A
• chrX-154030695-G-C
• chrX-154030695-G-T

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.Ala378Val (NM_004992) variant in MECP2 is 0.014% in East Asian sub population in gnomAD, which is high enough to meet BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala378Val variant is observed in at least 2 unaffected individuals (PMID 15737703)(BS2). In summary, the p.Ala378Val variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170175/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.00013 (0 hom. 37 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:8
• Conservation: PhyloP100: 2.85
• 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 -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.1169C>T	p.Ala390Val	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1133C>T	p.Ala378Val	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.854C>T	p.Ala285Val	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.1169C>T	p.Ala390Val	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1133C>T	p.Ala378Val	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1133C>T	p.Ala378Val	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 11 AN: 109524 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000966

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000287

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000153

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000515 AC: 9 AN: 174908 AF XY: 0.0000319

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.000146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000515

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000129 AC: 141 AN: 1093137 Hom.: 0 Cov.: 35 AF XY: 0.000103 AC XY: 37 AN XY: 359747

African (AFR) AF: 0.00 AC: 0 AN: 26266

American (AMR) AF: 0.0000285 AC: 1 AN: 35043

Ashkenazi Jewish (ASJ) AF: 0.0000518 AC: 1 AN: 19296

East Asian (EAS) AF: 0.000796 AC: 24 AN: 30157

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53895

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38888

Middle Eastern (MID) AF: 0.000266 AC: 1 AN: 3764

European-Non Finnish (NFE) AF: 0.000131 AC: 110 AN: 839963

Other (OTH) AF: 0.0000654 AC: 3 AN: 45865

GnomAD4 genome AF: 0.000100 AC: 11 AN: 109524 Hom.: 0 Cov.: 22 AF XY: 0.0000315 AC XY: 1 AN XY: 31794

African (AFR) AF: 0.0000333 AC: 1 AN: 30008

American (AMR) AF: 0.0000966 AC: 1 AN: 10356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2610

East Asian (EAS) AF: 0.000287 AC: 1 AN: 3484

South Asian (SAS) AF: 0.00 AC: 0 AN: 2517

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000153 AC: 8 AN: 52269

Other (OTH) AF: 0.00 AC: 0 AN: 1475

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000743 AC: 9

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
1	-	1	not provided (2)
-	-	2	Rett syndrome (2)
-	-	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	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.050	N
REVEL	Uncertain	0.47
Sift	Benign	0.11	T
Sift4G	Benign	0.28	T
Polyphen		0.90	P
Vest4		0.11
MutPred		0.35		Gain of methylation at K377 (P = 0.0497)
MVP		0.82
ClinPred		0.067	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.42
Mutation Taster		=99/1	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: rs201314910; hg19: chrX-153296146;