rs5986954

Positions:

• chrX-154083842-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.62+13762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 110,977 control chromosomes in the GnomAD database, including 501 homozygotes. There are 2,334 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 0.080 (501 hom., 2334 hem., cov: 21)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.62+13762T>C		intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.26+8342T>C		intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.26+8342T>C		intron_variant		1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000453960.7	c.62+13762T>C		intron_variant		1	NM_001110792.2	ENSP00000395535

Frequencies

GnomAD3 genomes AF: 0.0803 AC: 8904 AN: 110923 Hom.: 498 Cov.: 21 AF XY: 0.0700 AC XY: 2320 AN XY: 33145

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0212

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0710

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

GnomAD4 genome AF: 0.0805 AC: 8932 AN: 110977 Hom.: 501 Cov.: 21 AF XY: 0.0703 AC XY: 2334 AN XY: 33209

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0460

Gnomad4 ASJ AF: 0.0212

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.0414

Gnomad4 NFE AF: 0.0431

Gnomad4 OTH AF: 0.0807

Alfa AF: 0.0703 Hom.: 418

Bravo AF: 0.0873

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.35
DANN	Benign	0.43

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: rs5986954; hg19: chrX-153349295;