chrX-154030987-C-T

Variant names:

• chrX-154030987-C-T
• rs782239416
• NM_001110792.2:c.877G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala281Thr variant in MECP2 (NM_004992.3) is 0.037% in the South 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.Ala281Thr variant is observed in at least 8 unaffected individuals (internal database - Invitae) (BS2). In summary, the p.Ala281Thr variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10558543/MONDO:0010726/036

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000056 (0 hom. 19 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 2.17
• 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 -12 ACMG points.

• 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.877G>A	p.Ala293Thr	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.841G>A	p.Ala281Thr	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.562G>A	p.Ala188Thr	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.877G>A	p.Ala293Thr	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.841G>A	p.Ala281Thr	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.841G>A	p.Ala281Thr	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 111988 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000937 AC: 17 AN: 181466 AF XY: 0.000104

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000556 AC: 61 AN: 1098021 Hom.: 0 Cov.: 35 AF XY: 0.0000523 AC XY: 19 AN XY: 363447

African (AFR) AF: 0.000265 AC: 7 AN: 26401

American (AMR) AF: 0.000170 AC: 6 AN: 35202

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

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.000462 AC: 25 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40325

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4137

European-Non Finnish (NFE) AF: 0.0000249 AC: 21 AN: 842131

Other (OTH) AF: 0.00 AC: 0 AN: 46085

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 111988 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34170

African (AFR) AF: 0.0000975 AC: 3 AN: 30780

American (AMR) AF: 0.0000934 AC: 1 AN: 10707

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53076

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000107 AC: 13

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.44
Sift	Benign	0.11	T
Sift4G	Benign	0.56	T
Polyphen		0.92	P
Vest4		0.13
MutPred		0.23		Gain of phosphorylation at A281 (P = 0.0408)
MVP		0.99
ClinPred		0.021	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
gMVP		0.88
Mutation Taster		=98/2	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: rs782239416; hg19: chrX-153296438; COSMIC: COSV57658195; COSMIC: COSV57658195;