X-154031435-G-C

Variant names:

• chrX-154031435-G-C
• rs61748385
• NM_001110792.2:c.429C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.393C>G (p.Ala131=) variant in MECP2 (NM_004992.3) is 0.1698% in the Ashkenazi Jewish 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 silent c.393C>G (p.Ala131=) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary, the c.393C>G (p.Ala131=) variant in MECP2 is classified as Benign based on the ACMG/AMP criteria (BA1, BP4, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170296/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00013 (0 hom. 39 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: 0.276
• Publications: 1 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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.429C>G	p.Ala143Ala	synonymous	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.393C>G	p.Ala131Ala	synonymous	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.114C>G	p.Ala38Ala	synonymous	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.429C>G	p.Ala143Ala	synonymous	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.393C>G	p.Ala131Ala	synonymous	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.393C>G	p.Ala131Ala	synonymous	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 26 AN: 112174 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00567

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000652

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000215 AC: 39 AN: 181568 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00174

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000131 AC: 144 AN: 1097962 Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 39 AN XY: 363320

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.000114 AC: 4 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00181 AC: 35 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54136

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.0000903 AC: 76 AN: 841929

Other (OTH) AF: 0.000391 AC: 18 AN: 46088

GnomAD4 genome AF: 0.000232 AC: 26 AN: 112174 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34334

African (AFR) AF: 0.00 AC: 0 AN: 30862

American (AMR) AF: 0.00 AC: 0 AN: 10627

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 15 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2719

European-Finnish (FIN) AF: 0.000652 AC: 4 AN: 6135

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

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53155

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.000304 Hom.: 2

Bravo AF: 0.000181

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	not provided (2)
-	-	2	Rett syndrome (2)
-	-	1	History of neurodevelopmental disorder (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
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.0
DANN	Benign	0.57
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61748385; hg19: chrX-153296886; COSMIC: COSV57652119; COSMIC: COSV57652119;