chrX-154093299-T-C

Variant names:

• chrX-154093299-T-C
• rs5945175
• NM_001110792.2:c.62+4305A>G

Variant summary

Our verdict is Benign. The variant received -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
• 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=-0.89).
• 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 the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2911 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.62+4305A>G		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-98-992A>G		intron_variant	Intron 1 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.62+4305A>G		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.-98-992A>G		intron_variant	Intron 1 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 2912 AN: 110872 Hom.: 60 Cov.: 21

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

African (AFR) AF: 0.00511 AC: 156 AN: 30528

American (AMR) AF: 0.00878 AC: 91 AN: 10364

Ashkenazi Jewish (ASJ) AF: 0.0901 AC: 237 AN: 2630

East Asian (EAS) AF: 0.00113 AC: 4 AN: 3555

South Asian (SAS) AF: 0.0413 AC: 109 AN: 2638

European-Finnish (FIN) AF: 0.0211 AC: 123 AN: 5826

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.0406 AC: 2151 AN: 52975

Other (OTH) AF: 0.0246 AC: 37 AN: 1507

Alfa AF: 0.0246 Hom.: 429

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
PhyloP100		-0.23
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: rs5945175; hg19: chrX-153358757;