X-154039017-C-T

Variant names:

• chrX-154039017-C-T
• rs3027935
• NM_001110792.2:c.63-6460G>A

Variant summary

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

The NM_001110792.2(MECP2):​c.63-6460G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 111,677 control chromosomes in the GnomAD database, including 669 homozygotes. There are 3,184 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 0.10 (669 hom., 3184 hem., cov: 22)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.816

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.63-6460G>A		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.27-6460G>A		intron_variant	Intron 2 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.63-6460G>A		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.27-6460G>A		intron_variant	Intron 2 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.104 AC: 11570 AN: 111625 Hom.: 666 Cov.: 22 AF XY: 0.0937 AC XY: 3173 AN XY: 33859

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0792

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0857

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

GnomAD4 genome AF: 0.104 AC: 11591 AN: 111677 Hom.: 669 Cov.: 22 AF XY: 0.0939 AC XY: 3184 AN XY: 33921

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.0790

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.0366

Gnomad4 FIN AF: 0.0546

Gnomad4 NFE AF: 0.0679

Gnomad4 OTH AF: 0.0945

Alfa AF: 0.0517 Hom.: 350

Bravo AF: 0.110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.27
DANN	Benign	0.60

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: rs3027935; hg19: chrX-153304468;