rs2239464

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.62+14626C>T		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.26+9206C>T		intron_variant	Intron 2 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.62+14626C>T		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.26+9206C>T		intron_variant	Intron 2 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.342 AC: 37939 AN: 110907 Hom.: 5984 Cov.: 23 AF XY: 0.344 AC XY: 11382 AN XY: 33131

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

Gnomad4 AFR AF: 0.546

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.612

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.379

Alfa AF: 0.237 Hom.: 10199

Bravo AF: 0.374

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Benign:1

Dec 02, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). The computational splicing predictor SpliceAI do not support significant splicing alteration (score of <=0.1). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2239464; hg19: chrX-153348431;