rs2239464

Positions:

• chrX-154082978-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (5993 hom., 11427 hem., cov: 23)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• 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/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.62+14626C>T		intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.26+9206C>T		intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.26+9206C>T		intron_variant		1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000453960.7	c.62+14626C>T		intron_variant		1	NM_001110792.2	ENSP00000395535

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

Not reported in ClinVar

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;