rs1734787

Positions:

• chrX-154059995-A-C
• chrX-154059995-A-G

Variant summary

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

The NM_001110792.2(MECP2):​c.63-27438T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 751,542 control chromosomes in the GnomAD database, including 7,905 homozygotes. There are 32,788 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 0.18 (2116 hom., 6281 hem., cov: 22)
  • Exomes 𝑓: 0.14 (5789 hom. 26507 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.645

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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.63-27438T>G		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.27-27438T>G		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.27-27438T>G		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.63-27438T>G		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 19931 AN: 110819 Hom.: 2117 Cov.: 22 AF XY: 0.190 AC XY: 6271 AN XY: 33033

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.0364

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.292

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.137 AC: 87588 AN: 640668 Hom.: 5789 Cov.: 28 AF XY: 0.138 AC XY: 26507 AN XY: 192298

Gnomad4 AFR exome AF: 0.0808

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.779

Gnomad4 SAS exome AF: 0.561

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.180 AC: 19932 AN: 110874 Hom.: 2116 Cov.: 22 AF XY: 0.190 AC XY: 6281 AN XY: 33098

Gnomad4 AFR AF: 0.0883

Gnomad4 AMR AF: 0.365

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.769

Gnomad4 SAS AF: 0.590

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.241

Alfa AF: 0.170 Hom.: 5181

Bravo AF: 0.197

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1734787; hg19: chrX-153325446;