rs267608459

Variant names:

• chrX-154032197-TCTTA-T
• rs267608459
• NM_001110792.2:c.413+6_413+9delTAAG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.413+6_413+9delTAAG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000647 in 1,081,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★★). The gene MECP2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000065 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 splice_region, intron
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3 O:1
• Conservation: PhyloP100: 6.04
• 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: 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

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant X-154032197-TCTTA-T is Benign according to our data. Variant chrX-154032197-TCTTA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 156059.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAdExome4 at 7 XL,Unknown,AD gene.

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+6_413+9delTAAG		splice_region intron	N/A	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.377+6_377+9delTAAG		splice_region intron	N/A	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.98+6_98+9delTAAG		splice_region 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+6_413+9delTAAG		splice_region intron	N/A	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.377+6_377+9delTAAG		splice_region intron	N/A	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.377+6_377+9delTAAG		splice_region intron	N/A	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183016 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000647 AC: 7 AN: 1081701 Hom.: 0 AF XY: 0.00000574 AC XY: 2 AN XY: 348439

African (AFR) AF: 0.00 AC: 0 AN: 26065

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19274

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30139

South Asian (SAS) AF: 0.00 AC: 0 AN: 53764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4079

European-Non Finnish (NFE) AF: 0.00000363 AC: 3 AN: 827146

Other (OTH) AF: 0.0000220 AC: 1 AN: 45544

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267608459; hg19: chrX-153297648;