rs2239464

Variant names:

• chrX-154082978-G-A
• rs2239464
• NM_001110792.2:c.62+14626C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001110792.2(MECP2):​c.62+14626C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 110,958 control chromosomes in the GnomAD database, including 5,993 homozygotes. There are 11,427 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (5993 hom., 11427 hem., cov: 23)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.113
• Publications: 29 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-154082978-G-A is Benign according to our data. Variant chrX-154082978-G-A is described in ClinVar as Benign. ClinVar VariationId is 3602015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.62+14626C>T		intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.26+9206C>T		intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.-422+9206C>T		intron	N/A	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.62+14626C>T		intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.26+9206C>T		intron	N/A	ENSP00000301948.6
	MECP2	ENST00000496908.5	TSL:1	n.157+13835C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.342 AC: 37939 AN: 110907 Hom.: 5984 Cov.: 23

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.0366

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.614

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.342 AC: 37996 AN: 110958 Hom.: 5993 Cov.: 23 AF XY: 0.344 AC XY: 11427 AN XY: 33192

African (AFR) AF: 0.546 AC: 16625 AN: 30454

American (AMR) AF: 0.452 AC: 4714 AN: 10425

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 630 AN: 2622

East Asian (EAS) AF: 0.780 AC: 2743 AN: 3515

South Asian (SAS) AF: 0.612 AC: 1579 AN: 2582

European-Finnish (FIN) AF: 0.196 AC: 1170 AN: 5957

Middle Eastern (MID) AF: 0.353 AC: 76 AN: 215

European-Non Finnish (NFE) AF: 0.186 AC: 9858 AN: 52986

Other (OTH) AF: 0.379 AC: 576 AN: 1519

Alfa AF: 0.254 Hom.: 15296

Bravo AF: 0.374

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.90
PhyloP100		-0.11

Splicing

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

Other links and lift over

dbSNP: rs2239464; hg19: chrX-153348431;