rs7050901

Variant names:

• chrX-154048859-C-T
• rs7050901
• NM_001110792.2:c.63-16302G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001110792.2(MECP2):​c.63-16302G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0661 in 111,581 control chromosomes in the GnomAD database, including 274 homozygotes. There are 1,959 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 0.066 (274 hom., 1957 hem., cov: 23)
  • Exomes 𝑓: 0.033 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.720
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.63-16302G>A		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.27-16302G>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.63-16302G>A		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.27-16302G>A		intron_variant	Intron 2 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 7359 AN: 111403 Hom.: 270 Cov.: 23

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0318

Gnomad ASJ AF: 0.0370

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0459

Gnomad OTH AF: 0.0622

GnomAD4 exome AF: 0.0328 AC: 4 AN: 122 Hom.: 0 Cov.: 0 AF XY: 0.0556 AC XY: 2 AN XY: 36

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0323 AC: 3 AN: 93

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0385 AC: 1 AN: 26

Other (OTH) AF: 0.00 AC: 0 AN: 3

GnomAD4 genome AF: 0.0662 AC: 7375 AN: 111459 Hom.: 274 Cov.: 23 AF XY: 0.0580 AC XY: 1957 AN XY: 33735

African (AFR) AF: 0.133 AC: 4073 AN: 30545

American (AMR) AF: 0.0317 AC: 334 AN: 10550

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 98 AN: 2649

East Asian (EAS) AF: 0.0110 AC: 39 AN: 3557

South Asian (SAS) AF: 0.0116 AC: 31 AN: 2667

European-Finnish (FIN) AF: 0.0408 AC: 247 AN: 6047

Middle Eastern (MID) AF: 0.0421 AC: 9 AN: 214

European-Non Finnish (NFE) AF: 0.0459 AC: 2435 AN: 53040

Other (OTH) AF: 0.0720 AC: 109 AN: 1514

Alfa AF: 0.0634 Hom.: 773

Bravo AF: 0.0696

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0060
DANN	Benign	0.58
PhyloP100		-0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7050901; hg19: chrX-153314310;