rs1734792

Positions:

• chrX-154075609-C-A
• chrX-154075609-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001110792.2(MECP2):​c.62+21995G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 110,120 control chromosomes in the GnomAD database, including 2,527 homozygotes. There are 7,213 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 0.22 (2527 hom., 7213 hem., cov: 22)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.256

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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.62+21995G>T		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.26+16575G>T		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.26+16575G>T		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.62+21995G>T		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 23850 AN: 110070 Hom.: 2527 Cov.: 22 AF XY: 0.222 AC XY: 7197 AN XY: 32364

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.0397

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.217 AC: 23858 AN: 110120 Hom.: 2527 Cov.: 22 AF XY: 0.222 AC XY: 7213 AN XY: 32424

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.384

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.751

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.263

Alfa AF: 0.179 Hom.: 1813

Bravo AF: 0.242

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1734792; hg19: chrX-153341060;