chrX-154033423-G-C

Position:

• chrX-154033423-G-C

Variant summary

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

The NM_001110792.2(MECP2):​c.63-866C>G 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 0.79 (25869 hom., 24959 hem., cov: 22)
  • Exomes 𝑓: 0.79 (4 hom. 12 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241

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]

MECP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.63-866C>G		intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.27-866C>G		intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.63-866C>G		intron_variant		1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.27-866C>G		intron_variant		1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.795 AC: 87369 AN: 109930 Hom.: 25873 Cov.: 22 AF XY: 0.775 AC XY: 24915 AN XY: 32148

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.961

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.705

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.745

GnomAD4 exome AF: 0.786 AC: 22 AN: 28 Hom.: 4 Cov.: 0 AF XY: 0.750 AC XY: 12 AN XY: 16

Gnomad4 ASJ exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.647

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.795 AC: 87403 AN: 109987 Hom.: 25869 Cov.: 22 AF XY: 0.775 AC XY: 24959 AN XY: 32215

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.782

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.842

Gnomad4 NFE AF: 0.859

Gnomad4 OTH AF: 0.744

Alfa AF: 0.716 Hom.: 2999

Bravo AF: 0.778

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.7
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3027933; hg19: chrX-153298874;