X-154030489-C-T

Variant names:

• chrX-154030489-C-T
• rs267608626
• NM_001110792.2:c.1375G>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.Ala447Thr (NM_004992.3) variant in MECP2 is 0.02% in East Asian sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala447Thr variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2). In summary, the p.Ala447Thr variant in MECP2 is classified as benign based on the ACMG/AMP criteria (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170236/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000084 (0 hom. 24 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 0.193
• 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: 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.1375G>A	p.Ala459Thr	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1339G>A	p.Ala447Thr	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.1060G>A	p.Ala354Thr	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.1375G>A	p.Ala459Thr	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1339G>A	p.Ala447Thr	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1339G>A	p.Ala447Thr	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111503 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.0000763 AC: 14 AN: 183432 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000216

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000733

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000838 AC: 92 AN: 1098214 Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 24 AN XY: 363572

African (AFR) AF: 0.000114 AC: 3 AN: 26402

American (AMR) AF: 0.000114 AC: 4 AN: 35207

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

East Asian (EAS) AF: 0.000265 AC: 8 AN: 30204

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54149

European-Finnish (FIN) AF: 0.0000741 AC: 3 AN: 40502

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

European-Non Finnish (NFE) AF: 0.0000807 AC: 68 AN: 842132

Other (OTH) AF: 0.000108 AC: 5 AN: 46097

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111553 Hom.: 0 Cov.: 22 AF XY: 0.000148 AC XY: 5 AN XY: 33739

African (AFR) AF: 0.0000976 AC: 3 AN: 30743

American (AMR) AF: 0.0000947 AC: 1 AN: 10558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.000383 AC: 1 AN: 2614

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53020

Other (OTH) AF: 0.000655 AC: 1 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Rett syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (1)
-	-	1	not specified (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.19
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.38
Sift	Benign	0.078	T
Sift4G	Benign	0.47	T
Polyphen		0.82	P
Vest4		0.093
MVP		0.96
ClinPred		0.040	T
GERP RS		2.9
Varity_R		0.090
gMVP		0.15
Mutation Taster		=91/9	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: rs267608626; hg19: chrX-153295940;