X-154032189-G-C

Variant names:

• chrX-154032189-G-C
• rs267608461
• NM_001110792.2:c.413+18C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.377+18C>G variant (NM_004992.3) in MECP2 is 0.01% in Latino 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). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). In summary, the c.377+18C>G variant in MECP2 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA199493/MONDO:0010726/016

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000066 (0 hom. 3 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4 O:1
• Conservation: PhyloP100: 0.735
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.413+18C>G		intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.377+18C>G		intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.98+18C>G		intron	N/A	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.413+18C>G		intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.377+18C>G		intron	N/A	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.377+18C>G		intron	N/A	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 113028 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000932

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: 0.0000219 AC: 4 AN: 182750 AF XY: 0.0000297

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000661 AC: 7 AN: 1059552 Hom.: 0 Cov.: 26 AF XY: 0.00000906 AC XY: 3 AN XY: 331208

African (AFR) AF: 0.0000390 AC: 1 AN: 25640

American (AMR) AF: 0.000142 AC: 5 AN: 35159

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19159

East Asian (EAS) AF: 0.00 AC: 0 AN: 30045

South Asian (SAS) AF: 0.00 AC: 0 AN: 53217

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4015

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 806983

Other (OTH) AF: 0.00 AC: 0 AN: 44859

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 113082 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35228

African (AFR) AF: 0.0000320 AC: 1 AN: 31244

American (AMR) AF: 0.0000931 AC: 1 AN: 10739

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3608

South Asian (SAS) AF: 0.00 AC: 0 AN: 2773

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6291

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53325

Other (OTH) AF: 0.00 AC: 0 AN: 1540

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Rett syndrome (2)
-	1	-	Autism, susceptibility to, X-linked 3 (1)
-	-	1	not specified (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.57
PhyloP100		0.73
PromoterAI		0.050	Neutral
Mutation Taster		=100/0	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: rs267608461; hg19: chrX-153297640;