rs146107517

Variant names:

• chrX-154032209-G-T
• rs146107517
• NM_001110792.2:c.411C>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.Ile125= variant in MECP2 (NM_004992) is 0.394% in 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.Ile125= variant is observed in at least 2 unaffected individuals (PMID 11055898, 20479760, RettBASE proband id 4623, 4624) (BS2). In summary, the p.Ile125= variant in MECP2 is classified as Benign based on the ACMG/AMP criteria applied (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211309/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., 18 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (2 hom. 429 hem.)
• Consequence: MECP2 NM_001110792.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003851
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: 7.63
• 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 -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.411C>A	p.Ile137Ile	splice_region synonymous	Exon 2 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.375C>A	p.Ile125Ile	splice_region synonymous	Exon 3 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001386137.1		c.-186C>A		splice_region	Exon 4 of 6	NP_001373066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.411C>A	p.Ile137Ile	splice_region synonymous	Exon 2 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.375C>A	p.Ile125Ile	splice_region synonymous	Exon 3 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.375C>A	p.Ile125Ile	splice_region synonymous	Exon 3 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000700 AC: 79 AN: 112933 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00469

Gnomad FIN AF: 0.000159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000939 AC: 172 AN: 183190 AF XY: 0.00123

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.000918

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00107 AC: 1168 AN: 1092411 Hom.: 2 Cov.: 30 AF XY: 0.00120 AC XY: 429 AN XY: 358097

African (AFR) AF: 0.0000761 AC: 2 AN: 26297

American (AMR) AF: 0.0000852 AC: 3 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00274 AC: 53 AN: 19351

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00361 AC: 195 AN: 53969

European-Finnish (FIN) AF: 0.0000988 AC: 4 AN: 40497

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4113

European-Non Finnish (NFE) AF: 0.00103 AC: 859 AN: 836884

Other (OTH) AF: 0.00109 AC: 50 AN: 45919

GnomAD4 genome AF: 0.000699 AC: 79 AN: 112987 Hom.: 1 Cov.: 24 AF XY: 0.000512 AC XY: 18 AN XY: 35141

African (AFR) AF: 0.0000320 AC: 1 AN: 31216

American (AMR) AF: 0.000279 AC: 3 AN: 10753

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.00470 AC: 13 AN: 2766

European-Finnish (FIN) AF: 0.000159 AC: 1 AN: 6270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00107 AC: 57 AN: 53295

Other (OTH) AF: 0.00 AC: 0 AN: 1541

Alfa AF: 0.00103 Hom.: 14

Bravo AF: 0.000578

EpiCase AF: 0.00131

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	2	not provided (3)
-	-	2	Rett syndrome (2)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.79
PhyloP100		7.6
PromoterAI		-0.10	Neutral
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.078
SpliceAI score (max)		0.020		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: rs146107517; hg19: chrX-153297660;