rs5987194

chrX-154036016-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001110792.2(MECP2):c.63-3459G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.81 (26828 hom., 25062 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.77

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BS2: High Homozygotes in GnomAd at 26827 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.63-3459G>C		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.27-3459G>C		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.27-3459G>C		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.63-3459G>C		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.809 AC: 88580 AN: 109494 Hom.: 26827 Cov.: 22 AF XY: 0.788 AC XY: 25022 AN XY: 31762

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.755

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

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.809 AC: 88615 AN: 109538 Hom.: 26828 Cov.: 22 AF XY: 0.788 AC XY: 25062 AN XY: 31816

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.780

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.857

Gnomad4 NFE AF: 0.860

Gnomad4 OTH AF: 0.754

Alfa AF: 0.832 Hom.: 7147

Bravo AF: 0.794

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.85
Dann	Benign	0.37

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: rs5987194; hg19: chrX-153301467;