rs5945175

chrX-154093299-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001110792.2(MECP2):c.62+4305A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 110,926 control chromosomes in the GnomAD database, including 60 homozygotes. There are 806 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 0.026 (60 hom., 806 hem., cov: 21)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230

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=-0.89).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0262 (2911/110926) while in subpopulation SAS AF= 0.0413 (109/2638). AF 95% confidence interval is 0.0392. There are 60 homozygotes in gnomad4. There are 806 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 60 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.62+4305A>G		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.-98-992A>G		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.-98-992A>G		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.62+4305A>G		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 2912 AN: 110872 Hom.: 60 Cov.: 21 AF XY: 0.0244 AC XY: 806 AN XY: 33080

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00879

Gnomad ASJ AF: 0.0901

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0249

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

GnomAD4 genome AF: 0.0262 AC: 2911 AN: 110926 Hom.: 60 Cov.: 21 AF XY: 0.0243 AC XY: 806 AN XY: 33144

Gnomad4 AFR AF: 0.00511

Gnomad4 AMR AF: 0.00878

Gnomad4 ASJ AF: 0.0901

Gnomad4 EAS AF: 0.00113

Gnomad4 SAS AF: 0.0413

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0345 Hom.: 226

Bravo AF: 0.0233

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.9
Dann	Benign	0.45

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: rs5945175; hg19: chrX-153358757;