X-154031941-A-G

Variant names:

• chrX-154031941-A-G
• rs2075596
• NM_001110792.2:c.413+266T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001110792.2(MECP2):​c.413+266T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (28382 hom., 27451 hem., cov: 24)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.0690
• Publications: 23 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant X-154031941-A-G is Benign according to our data. Variant chrX-154031941-A-G is described in ClinVar as Benign. ClinVar VariationId is 156056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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+266T>C		intron	N/A	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.377+266T>C		intron	N/A	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.98+266T>C		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+266T>C		intron	N/A	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.377+266T>C		intron	N/A	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.377+266T>C		intron	N/A	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.831 AC: 92717 AN: 111618 Hom.: 28382 Cov.: 24

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.775

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.831 AC: 92769 AN: 111672 Hom.: 28382 Cov.: 24 AF XY: 0.811 AC XY: 27451 AN XY: 33842

African (AFR) AF: 0.948 AC: 29138 AN: 30737

American (AMR) AF: 0.631 AC: 6681 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 2074 AN: 2648

East Asian (EAS) AF: 0.236 AC: 839 AN: 3562

South Asian (SAS) AF: 0.407 AC: 1099 AN: 2699

European-Finnish (FIN) AF: 0.865 AC: 5169 AN: 5976

Middle Eastern (MID) AF: 0.699 AC: 153 AN: 219

European-Non Finnish (NFE) AF: 0.863 AC: 45779 AN: 53041

Other (OTH) AF: 0.774 AC: 1180 AN: 1525

Alfa AF: 0.817 Hom.: 17250

Bravo AF: 0.817

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	not specified (1)
-	-	1	Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.6
DANN	Benign	0.72
PhyloP100		0.069
PromoterAI		0.0047	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2075596; hg19: chrX-153297392;